Syndactyly Of Toes Research Articles

PATH-67. SHH/GLI3 SIGNALOPATHIES AND NEURO-ONCO-GENETIC COUNSELING : A TUNISIAN PEDIGREE

Abstract Here, we present a 3-generation pedigree of a Tunisian non-consanguineous family with six offspring affected by heterogeneous forms of the GLI3-related PHS spectrum. Our aim was to assess the neuro-onco-genetic risks and provide counseling for appropriate clinical follow-up. A non-consanguineous couple was referred to our genetic counseling due to the termination of their first pregnancy, which was diagnosed with multiple congenital anomalies. An autopsy examination, including pathological and radiographic analysis, was conducted. Furthermore, a medical genetic assessment considering a family history spanning over three generations as well as cytogenetic analysis were carried out. The index case was diagnosed with GLI3-related PHS based on facial dysmorphic features, auricular malformations, and unilateral postaxial toe syndactyly, along with brain macro-calcifications. The index case's father and his brother exhibited facial dysmorphic features. Furthermore, two cousins from one of their paternal uncles presented another form, associated respectively with unilateral renal agenesis and unilateral hand agenesis. The remaining three cases, who belong to the first generation, and passed away during infancy, exhibited the same condition, associated to congenital heart defect in one of them. The heterogeneity of GLI3-related overlapping conditions (SHH/GLI3 signalopathies) result from the location of GLI3 mutations in different domains of the gene, as well as the resulting functional balance between activating and repressive forms of GLI3 during development. The report of a late diagnosis of GLI3-related PHS following the discovery of hypothalamic hamartomas as well as the description of a new nonsense germline mutation in a child with Greig syndrome and medulloblastoma, support that neuro-oncological investigation of GLI3 families could be beneficial.

A somatic splice-site variant in PIK3R1 in a patient with vascular overgrowth and low immunoglobulin levels: A case report.

The PI3K/AKT pathway, extensively studied in cancer, is vital for regulating cell metabolism, differentiation, and proliferation. Pathogenic variants in the PIK3R1 gene, which encodes three regulatory units of class IA PI3Ks, have been found in affected tissue of individuals with vascular lesions. These variants predominantly occur in the iSH2 domain, disrupting inhibitory contacts with the catalytic unit and leading to PI3K activation. Germline variants in this gene are also linked to an immunological condition called Activated PI3K delta syndrome type 2 (APDS2). This is a case report and literature review. Clinical data were retrieved from medical records. A male patient presented with extensive vascular malformation covering over 90% of his body, along with complete 2-3 toe syndactyly, suggesting a vascular malformation syndrome called PROS. Low levels of IgA and IgG were detected. The patient achieved his developmental milestones and had above-average weight, height, and head circumference. Exome sequencing of skin and blood DNA revealed a de novo variant in PIK3R1 (c.1746-2A>G, p.?) in 9% of the patient's blood cells and 25% of cultured fibroblasts. Initially, classified as a variant of uncertain significance, this variant was later confirmed to be the cause. This is the first intronic SNV in a canonical splice site within iSH2 described, highlighting the importance of iSH2 in the regulation of the PI3K/AKT pathway and its involvement in the development of vascular overgrowth and antibody deficiency.

Oculofaciocardiodental syndrome caused by a novel BCOR variant

Oculofaciocardiodental syndrome is caused by variants in the BCL6 corepressor (BCOR) gene. We identified a novel heterozygous frameshift variant, NM_001123385.2(BCOR):c.2326del, that arose de novo in a Japanese girl with characteristic facial features, congenital heart disease, bilateral syndactyly of toes 2 and 3, congenital cataracts, dental abnormalities, and mild intellectual disability. Reports of BCOR variants are rare, and further case accumulation is warranted.

A novel homozygous nonsense mutation in NECTIN4 gene in a Pakistani family with ectodermal dysplasia syndactyly syndrome 1

BackgroundEctodermal dysplasia syndactyly syndrome 1 (EDSS1) is a rare hereditary disorder characterized by defects in teeth, hair, and nails in association with a fusion of the digits. Genetically, the disease phenotypes are caused by homozygous and compound heterozygous variants in NECTIN4 gene. ObjectiveThe main objective of the study was to identify the pathogenic sequence variant(s) for family screening and identification of carriers. MethodsIn the present study, the authors have investigated a large consanguineous family of Pakistani origin segregating autosomal recessive EDSS1. All the coding exons of the NECTIN4 gene were directly sequenced using gene-specific primers. ResultsThe affected individuals presented the classical EDSS1 clinical features including sparse hair, hypoplastic nails with thick flat discolored nail plates, peg-shaped, conical, and widely spaced teeth with enamel hypoplasia, proximal cutaneous syndactyly of fingers and toes. Sequence analysis of the coding region of the NECTIN4 identified a novel nonsense variant [c.163C>T; p.(Arg55*)] in exon-2 of the gene. Computational analysis of protein structure revealed that the variant induced premature termination at Arg55 located in Ig-like V-loop region leading to loss of Ig-C2 type domains and transmembrane region, and most likely Nectin-4 function will be lost. Study limitationGene expression studies are absent that would have strengthened the findings of computational analysis. ConclusionThe present study expanded the phenotypic and mutation spectrum of the NECTIN4 gene. Further, the study would assist in carrier testing and prenatal diagnosis of the affected families.

A novel syndrome associated with prenatal fentanyl exposure

A novel syndrome was suspected in individuals sharing short stature, microcephaly, distinctive facial features, and congenital anomalies. We enrolled 6 patients in an institutional review board approved study and evaluated medical history, findings, facial photographs, and test results across this original cohort. Four additional cases with similar findings were contributed by clinicians from outside institutions, bringing the number of reported cases to 10 and supporting the existence of this novel syndrome.The 6 individuals enrolled into the institutional review board approved study shared microcephaly, short stature, and distinctive facial features. Congenital malformations included cleft palate, talipes equinovarus or rocker bottom feet, and chordee or hypospadias. Short, broad thumbs, single palmar crease, and mild 2,3 toe syndactyly were present. A hypoplastic corpus callosum was noted in 3 of 5 with appropriate evaluation. Their growth and physical findings were suggestive of Smith-Lemli-Opitz syndrome. Biochemical studies shortly after delivery indicated abnormalities in the cholesterol metabolism pathway that subsequently resolved. No shared genomic or genetic cause was identified. All individuals were born after a pregnancy complicated by prenatal exposure to nonprescription opioids, particularly fentanyl, suggesting fentanyl as a teratogen.Prenatal fentanyl exposure possibly interfered with cholesterol metabolism, giving rise to findings resembling Smith-Lemli-Opitz syndrome. This novel syndrome is clinically recognizable. Four additional cases contributed clinically shared similar findings, increasing the number of cases to 10 and supporting a novel syndrome associated with prenatal fentanyl exposure. Assessment of Shepard and Bradford Hill criteria could be consistent with fentanyl as teratogen, though caution is necessary before assigning causality and data replication is needed.

Apert Syndrome with Agenesis of the Corpus Collosum - Case Report

Abstract Apert syndrome (Acrocephalosyndactylia type 1) belongs to the group of extremely rare congenital dysmorphic syndromes. It is characterized by craniostenosis with very early fusion of the skull and / or cranial base sutures, facial hypoplasia, symmetrical syndactyly of the fingers and toes and other systemic malformations. Multiple CNS abnormalities are common, but simultaneous occurrence of Apert syndrome and agenesis of corpus callosum is estimated about 10%. We present a male patient born after first, normal and controlled pregnancy and term, naturally birth, in which the Apert syndrome was diagnosed, based on the clinical presentation of the skull and face and syndactyly of fingers and toes. Neurological examination established generalized hypotonia and aggravated provocation of the primitive reflexes. Neurosonography showed complete agenesis of the corpus callosum, which makes this case a rare form of this syndrome. The head X-rays showed turricephalic skull shape and suture’s synostoses, which is demonstrated in more detail at computed tomography finding. The hands and feet X-rays showed bone synostosis of fingers and toes. The video-electroencephalogram recorded intermittent depression of electrocortical activity. There was conducted the multidisciplinary examination in order to examine the possibility of reconstructive and plastic surgical correction of the anomalies. The neurodevelopmental disorders in patients with Apert syndrome can be manifested by a variety of congenital malformations, but considering its rare occurrence, the significance of these abnormalities remains unknown.

The identification of a novel CCNQ gene tail extension variant contributing to syndactyly, telecanthus and anogenital and renal malformations syndrome.

The "toe syndactyly, telecanthus and anogenital and renal malformations" (STAR) syndrome is a rare X-linked dominant inherited kidney ciliopathy caused by CCNQ gene mutations. Here, we investigated the genotype and phenotype in the first two twin sisters with a novel tail extension CCNQ variant in Asia. Genetic variants of the pedigree were screened using whole-exome sequence analysis and validated by direct Sanger sequencing. The genetic function was investigated through cultured cells and zebrafish embryos transfected with mutant. The proband is suffered from end-stage renal disease, telecanthus, scoliosis, anal atresia, bilateral hydronephrosis pyeloureter dilation and hearing loss, while her twin sister had milder phenotypes. A novel heterozygous variant c.502_518delinsA (p.Val168SerfsTer173) in CCNQ gene was identified in the twins and their asymptomatic mosaic mother. The concurrent deletion of 17 bases and insertion of one base variant led to the loss of 5 amino acids, subsequently caused a 96 more amino acids tail extension delaying the appearance of stop codon. The loss-of-function variant of CCNQ not only led to the impaired expression of cyclin M but also increased the binding affinity of CDK10-cyclin M complex, which is different from the previous study. The research expanded the genotypic and phenotypic spectrum of STAR syndrome.

Classic Timothy Syndrome Associated With Bilateral Border Digit Syndactyly: A Case Series

Timothy syndrome (TS) is characterized by congenital long-QT arrhythmia and limb syndactyly. Patients who undergo syndactyly repair with undiagnosed TS may have their abnormal cardiac electrical activity unmasked during surgery. The purpose of this study was to detail the extremity phenotype seen in patients with TS, which may help hand surgeons in their preoperative assessment. This was a retrospective review of all patients with TS seen at our institution from 1998 to 2022. Descriptive statistics regarding their demographics, medical and surgical histories, and syndactyly phenotypes were obtained. Seven patients (5 males and 2 females) with TS were seen at our institution for multidisciplinary evaluation (median age at presentation was 23 months). Six patients had finger syndactyly and 5 had toe syndactyly. One patient did not have any extremity syndactyly and was noted to have a specific TS mutation known to lack musculoskeletal abnormalities. All patients with finger syndactyly had border digit involvement, with 5 out of 6 patients displaying syndactyly of the middle-ring and ring-little finger web spaces. Toe syndactyly was more heterogeneous, with 1 patient lacking any lower extremity syndactyly and others having variable involvement of the second-third, third-fourth, and fourth-little toe web spaces. Complexity ranged from simple to complete. Four patients had intraoperative cardiac events leading to TS diagnoses after surgery. Bilateral border digit hand syndactyly, with or without bilateral toe syndactyly, should raise concerns for TS and prompt further investigation into potential cardiac disease to avoid perioperative cardiac morbidity and mortality. Therapeutic V.

ODP408 Elevated DHEAS and Acute Hair Loss in an Adult Male with Trichorhinophalangeal Syndrome Type 1: a Case of Male PCOS

Abstract Background Male androgenic alopecia is a common cause of hair loss in both men and women. Although genetic and hormonal factors likely play a role, the etiology is mostly unknown. PCOS is a highly heritable disease with elevated prevalence of reproductive abnormalities in first-degree relatives (FDRs) of patients with PCOS, which may be due to an underlying genetic defect in steroidogenesis. A recent meta-analysis revealed that male FDRs of patients with PCOS had significantly increased levels of DHEAS compared with controls. We present a young adult male who developed acute hair loss with biochemical evidence of hyperandrogenism. Clinical Case A 21-year-old man presented for evaluation of hyperandrogenism after experiencing progressive loss of posterior patch of hair over 3 weeks. He also endorsed acne, intermittent headaches, striae, and difficulty losing weight for the past 2 years. He denied facial rounding, vision changes, and use of glucocorticoids or supplements. Physical examination was notable for height of 67 inches, BMI 30.5 mg/m 2, BP 120/78, recession of the frontotemporal and occipital hairline, sparse posterior scalp hair, bulbous nose, long philtrum, mild facial acne, 2, 3 toe syndactyly, and thin purple striae on bilateral flanks and axillae. Labs revealed elevated DHEAS 1065.7 mcg/dL (ref. 238.4-539.3) and normal 8 AM total testosterone of 382 ng/dL (240-871). Cosyntropin stimulation test revealed baseline cortisol level of 10.6 mcg/dL with ACTH of 22.2 pg/mL (5-46) and 60-minute cortisol level of 24.8 mcg/dL, 17-OH progesterone level 81 ng/dL (18-164), and 17-OH pregnenolone 1040 ng/dL (55-455). Workup for Cushing's revealed multiple normal midnight salivary cortisol levels and mild intermittent elevation of 24-hour urinary free cortisol levels. CT scan of the adrenals was negative for a mass. Exome sequencing revealed a heterozygous de novo pathogenic variant (c.1614_1615delTCinsAT: p. C538X) in the TRPS1 gene (NM_0141112.2). Family history was significant for a 20-year-old sister with PCOS and elevated DHEAS of 443 ug/dL (51-321). Mid-parental height was 69.6 inches. Conclusion Trichorhinophalangeal syndrome Type 1 (TRPS1) is a rare genetic disorder characterized by hair, craniofacial, and skeletal abnormalities such as androgenetic alopecia, bulbous nasal tip, and cone-shaped epiphyses. To our knowledge, the hair findings in TRPS are not associated with hyperandrogenism which prompted further investigation. Evaluation for endocrine causes of hyperandrogenism such as Cushing's disease, congenital adrenal hyperplasia, and adrenal tumor were negative. However, our patient's elevated DHEAS is likely due to male PCOS, as previously described in male FDRs of patients with PCOS. Thus, genetic susceptibility to PCOS and rare genetic syndromes should be considered in the differential diagnosis of young men with clinical and biochemical evidence of hyperandrogenism. Reference: Shan D et al. Reproductive Health in First-degree relatives of Patients with Polycystic Ovarian Syndrome: a Review and Meta-analysis. JCEM. 2022 Jan;107(1); 273-295. Presentation: No date and time listed

ERI1: A case report of an autosomal recessive syndrome associated with developmental delay and distal limb abnormalities.

ERI1 is an evolutionary conserved 3'-5' exonuclease with an important function in multiple RNA processing pathways. Although the molecular mechanisms in which ERI1 is involved have been studied extensively in model organisms, the pathology associated with ERI1 variants in humans has remained elusive because no case has been reported so far. Here, we present a case of a female patient with a homozygous nonsense variant in ERI1 gene. The patient exhibits mild intellectual disability, eyelid ptosis, and anomalies in her hands and feet (brachydactyly, clinodactyly, dysplastic/short nail of halluces, brachytelephalangy, short metacarpals, and toe syndactyly). This case report is the first of its kind and is invaluable for understanding ERI1 pathology in humans.

Amniotic Band Syndrome: A Report of Two Cases by a Primary Care Pediatrician

Objective – Amniotic Band Syndrome is a rare birth defect caused by strands of the amniotic sac that tangle around the baby’s body, causing injury. Amniotic Band Syndrome is not seen very often, but should be considered in every newborn with congenital anomalies. It can be diagnosed prenatally by ultrasound and is seen after birth. A team of specialists, a plastic surgeon, an orthopedic surgeon, a physiatrist, a psychologist and others should be included in the treatment and follow-up of children with Amniotic Band Syndrome, with an individual approach to every case. Case Report – The first patient, who was six years old, had malformations of the left hand, rudimentary fingers II and IV, missing finger III with circulatory ring, and clinodactyly of finger V. The second patient, eight months old, had the following malformations: syndactyly and circulatory ring on fingers II, III and IV of the left hand, and lymphedema; circulatory ring and lymphedema of the left lower leg, visible proximal parts of all five fingers; on the right foot syndactyly of toes I, II and III, a circular groove on toe IV, and lymphedema. Conclusion – Our cases have unique clinical presentations and therefore required reports. In such cases, the primary care pediatrician brings together a multidisciplinary team and provides further follow-up through rehabilitation and psychological treatment.

EP231: Ophthalmic findings associated with NEDD4L-related disorder: Novel finding in a patient and review of literature

NEDD4L (Neural Precursor Cell Expressed, Developmentally Down-Regulated 4-Like) (OMIM# * 606384) is an E3 ubiquitin ligase that regulates channel internalization and turnover. NEDD4L plays an important role in the initiation of neuronal migration in the cortex and ventricular zone of the fetal brain. Periventricular nodular heterotopia-7 (PVNH7) (OMIM# 617201) is caused by heterozygous pathogenic variants in the NEDD4L gene. There have been 14 reported patients with NEDD4L-related disorder and the common findings from these reports include radiographic findings of PVNH, developmental delay, toe syndactyly, and cleft palate.

Bilateral toe syndactyly – short review based on a case report

Non-syndromic toe syndactyly is a regular cause of foot malformation in children, bilateral form being less common. Syndactyly release procedures had few contraindications, as uncomplicated malformation or important patient comorbidities. Reported data show that corrective surgery using skin grafts is associated with an increased risk of infection, contractures, and web creep. Reconstruction surgical techniques, using flaps reduce morbidity, revision surgery, complication, may be associated with skin grafts and have superior aesthetic and functional results. We present a case of simple bilateral incomplete asymmetric toe syndactyly, released using a modified personalized local flaps reconstruction technique. The normal function and aesthetic of the feet was obtained, with no complications at one-year follow-up.

Surgical treatment in child’s congenital toe syndactyly: Risk factor of recurrence, complication and poor clinical outcomes

IntroductionSurgical treatment of toe syndactyly remains controversial. The strong demand from parents for a cosmetic release is increasing in our societies. But is it worth it? The objective was to assess medium-long term outcomes and to identify the risk factors of recurrence, complication and poor clinical outcomes. MethodsSixty-eight toe syndactylies (38 patients) undergoing surgery between 2008 and 2017 with a follow-up higher than two years were included consecutively and retrospectively. Four children (four syndactylies) were lost to follow-up and excluded. The mean age of the first surgery was 3.9 years old (0.8–16.7) and cohort mean follow-up was 6.9 years (2.8–11.2). In all patients, web release with a commissural dorsal flap was performed and associated a cutaneous resurfacing (spontaneous epithelialization, full-thickness skin graft taken from the popliteal crease, or a hyaluronic acid ester matrix). ResultsEighteen syndactylies (28.1%) in 14 patients recurred and one syndactyly required revision surgery. An age of surgery above two years was the only risk factor for recurrence found in univariate (OD = 0.27[0.08;0.85];p = 0.02) and multivariate studies (IC 95% = 0.05−0.68;p = 0.02). Seven complications (11.7%) in seven syndactylies (6 patients) were reported with six keloids (9.4%) and one scar retraction (1.6%). Each complication underwent an additional procedure. African ethnicity (N = 15) represents a risk factor (N = 4/15; OD = 0.12[0.009;0.97];p = 0.02) for keloids formation. Withey's average score is 4.9 (1–11), mean OxAFQ-C score was 52/60 (30–60), 67% would repeat the surgery and 69% felt satisfied at last follow-up. The simple syndactyly would appear less satisfied than complex or complicated (p = 0.02). ConclusionsSurgical treatment of child’s congenital syndactyly involves a risk of recurrence (28%) and potential complications (11,7%). Performed surgical procedure over two years old increase the risk of recurrence. African ethnicity is a risk factor in scarring complication. Only half of simple syndactylies are satisfied and prone to repeat the surgery.

Application of dorsal foot hexagonal flap for reconstruction of web space in fourth and fifth toe syndactyly combined with polydactyly

To explore the application of the dorsal foot hexagonal flap for reconstruction of the web space in the fourth and fifth toe syndactyly combined with polydactyly. Between May 2016 and October 2019, 27 patients (34 feet) with the fourth and fifth toe syndactyly combined with polydactyly were treated, including 12 males and 15 females with an average age of 22.8 months (range, 10 months to 8 years). There were 7 bilateral feet and 20 unilateral foot. Twenty-four of which were incomplete and 10 were complete syndactyly of the fourth and fifth toes, and the fifth toes showed various degrees of fibular deflection. All the 34 feet were treated with one-stage reconstruction of the toe web with the dorsal foot hexagonal flap, and the correction of the fibular deviation of the fifth toe was made by removing the tibial polydactyly and using the articular surface dressing or wedge osteotomy. All wounds healed by first intention without skin-frafting. All patients were followed up 6-36 months (mean, 18 months). There was no flexion contracture and obvious scar hyperplasia in all the patients, and the width and slope of the toe webs were normal. Three of the 34 webs developed web creep, and the rest of the toe webs were normal in depth. All 34 feet were corrected with peroneal fibular deviation, and the function of toe flexion was good. All parents of the children were satisfied with the outcome. The reconstruction of toe webs with dorsal foot hexagonal flaps for the treatment of the fourth and fifth toes syndactyly combined with polydactyly requires no skin graft. The operation is simple with high survival rate of the flap, the appearance and function of the toes are good, and the effectiveness is satisfactory.

Clinical and genetic analysis of a Chinese pedigree affected with Smith-Lemli-Opitz syndrome

To explore the clinical phenotype and pathogenic variants in a Chinese pedigree affected with Smith-Lemli-Opitz syndrome. Peripheral blood samples were collected from five members, including two affected ones, from the pedigree for the extraction of genomic DNA. Whole exome sequencing was carried out, and candidate variants were verified by Sanger sequencing as well as reverse transcription sequencing at the RNA level. The proband and another affected child from the pedigree showed mental retardation, dyskinesia, microcephaly, micrognathia, anteverted nares, and 2/3 toe syndactyly. The proband also had hypospadia, single upper incisor, and lower serum cholesterol level. Both children were found to harbor a paternally derived c.278C>T (p.T93M) variant and a maternally derived c.907G>A (p.G303R) variant of the DHCR7 gene. Both were known pathogenic mutations. The compound heterozygous mutations of c.278C>T (p.T93M) and c.907G>A (p.G303R) of the DHCR7 gene probably underlay the disease in this pedigree. Above finding has enabled early diagnosis and treatment of Smith-Lemli-Opitz syndrome.

The skin of birds' feet: Morphological adaptations of the plantar surface

The skin of the foot provides the interface between the bird and the substrate. The foot morphology involves the bone shape and the integument that is in contact with the substrate. The podotheca is a layer of keratinized epidermis forming scales that extends from the tarsometatarsus to the toe extremities. It varies in size, shape, amount of overlap and interacts with the degree of fusion of the toes (syndactyly). A study of toe shape and the podotheca provides insights on the adaptations of perching birds. Our analysis is based on micro-CT scans and scanning electron microscopy images of 21 species from 17 families, and includes examples with different orientations of the toes: zygodactyl (toes II and III forward), anisodactyl (toes II, III, and IV forward), and heterodactyl (toes III and IV forward). We show that in these three groups, the skin forms part of a perching adaptation that involves syndactyly to different degrees. However, syndactyly does not occur in Psittacidae that use their toes also for food manipulation. The syndactyly increases the sole surface and may reinforce adherence with the substrate. Scale shape and toe orientation are involved in functional adaptations to perch. Thus, both bone and skin features combine to form a pincer-like foot.

Proposed Phenotype for Females with a SETD5 Gene Variation: A Case Report

Background: SET domain containing 5 (SETD5) gene variants have been linked to developmental delays, craniofacial abnormalities, and intellectual disability (ID). Prior research examining the phenotypic presentation of individuals with SETD5 variations has been based largely on a male-dominated cohort and case studies. Evidence of a possible protective effect in females prompts the need for additional research on the neuropsychological presentation of females with a SETD5 variation. The current study aims to initiate this effort by discussing the neurocognitive profile of a right-handed 7-year-old Caucasian female with a diagnosed SETD5 variation. Methods and findings: The patient was referred for neuropsychological evaluation due to reported reading, writing, and fine motor difficulties. She presented with distinct dysmorphic features: head circumference <1st percentile, syndactyly of toes, clinodactyly of fifth fingers, and a long smooth philtrum with thin upper lip. Interpersonally, the patient was highly social. Cognitive testing revealed low average intelligence, with intact verbal/language functioning and impaired nonverbal/fluid reasoning abilities. Deficits were also observed in fine motor dexterity, visuomotor integration, attention, and broad academic achievement. The patient was ultimately referred for genetic testing, which revealed a de novo SETD5 frame shift variant resulting in a truncation of the gene copy near the end of the gene. Conclusion: This case study provides evidence for phenotypic differences between males and females with SETD5 gene variations. While males exhibit ID, females may present with significant deficits in nonverbal reasoning skills. Females may also display more fully developed social skills and a lack of repetitive stereotyped behaviors. Further research is warranted to clarify the unique presentation among females with SETD5 variations to better inform diagnosis and treatment planning.

SUN-691 Type 2 Diabetes Management in the Context of Smith-Magenis Syndrome: Case Report

Background: Smith-Magenis syndrome (SMS) is a rare condition caused by microdeletion chromosome 17p11.2 via RAI1 gene mutations, causing disrupted circadian sleep-wake patterns. Characteristic behaviors include: sleep disturbance, anxiety, maladaptive habits with self-injury (biting, picking, self-hugging, page-flipping) and outbursts. Characteristic features include: craniofacial abnormalities, short stature, 2/3 toe syndactyly, scoliosis, cardiac and genitourinary defects, hypotonia, peripheral neuropathy, epilepsy, childhood-onset truncal obesity, toileting difficulties. Management of adults with SMS span multiple disciplines: otolaryngology, audiology, ophthalmology, assessments of scoliosis, seizures, familial psychosocial health, sleep and behavioral changes with each medication. Annual assessments include: fasting lipids, thyroid panel, screening urinalysis. Patients should receive standard treatment for comorbid endocrine conditions, classically: hypercholesterolemia, hypothyroidism, growth hormone deficiency.Clinical Case: 49-year-old Hispanic female with history of SMS who presented to endocrinology for type 2 diabetes mellitus (T2DM) management. Past medical history includes T2DM with peripheral neuropathy, hypertension, hypercholesterolemia, intellectual disability, anxiety, recurrent genitourinary infections, sleep apnea. Physical exam is remarkable for macroglossia, truncal obesity, scoliosis, extremity excoriations evident of skin picking and xerosis, syndactyly of 2nd-3rd toes. Patient exhibited maladaptive behaviors like page-flipping, self-hugging, tantrums. Over the past 3 years, BMI remained in the obese range (>30 kg/m2) and A1c fluctuated from 7.0 to 10.6% averaging 8.8% (<5.7%). Patient is currently managed on insulin glargine, pioglitazone and liraglutide. She did not tolerate metformin due to dose-dependent diarrhea. Patient’s mother chose against SGLT2 inhibitors due to diminished genitourinary hygiene. T2DM management was complicated by patient behaviors, including nocturnal consumption of fructose-containing food and beverages, exercise intolerance, and associated caregiver fatigue.Conclusion: This case describes a patient managed for metabolic dysfunction in conjunction with a rare microdeletion disorder causing neurobehavioral disturbance with disrupted circadian sleep-wake patterns. The most difficult aspects of diabetes management included difficulty implementing lifestyle modifications to control the patient’s hyperglycemia.

Novel XRCC4 Mutations in an Infant With Microcephalic Primordial Dwarfism, Dilated Cardiomyopathy, Subclinical Hypothyroidism, and Early Death: Expanding the Phenotype Of XRCC4 Mutations

Microcephalic primordial dwarfism (MPD) is a group of clinically and genetically heterogeneous disorders which result in severe prenatal and postnatal growth failure. X-ray repair cross-complementing protein 4 (XRCC4) is a causative gene for an autosomal recessive form of MPD. The objective of this report is to describe novel XRCC4 mutations in a female infant with MPD, dilated cardiomyopathy, and subclinical hypothyroidism. Genetic testing was performed using a comprehensive next generation sequencing panel for MPD, followed by targeted XRCC4 gene sequencing. We report the case of a 970-gram, 35-cm, female infant (weight z score -5.05, length z score -4.71) born at 36 weeks and 3 days gestation. Physical examination revealed triangular facies, micrognathism, clinodactyly, and second and third toe syndactyly. Initial echocardiogram at birth was normal. Follow-up echocardiogram at 60 days of life revealed dilated cardiomyopathy with moderate left ventricular systolic dysfunction (ejection fraction was 40 to 45%), and anticongestive therapy was initiated. Thyroid testing revealed subclinical hypothyroidism with elevated thyroid-stimulating hormone of 13.0 μIU/mL (reference range is 0.3 to 5.0 μIU/mL) and normal free thyroxine by dialysis of 1.6 ng/dL (reference range is 0.8 to 2.0 ng/dL). Levothyroxine was initiated. Postnatal growth remained poor (weight z score at 3 months -4.93, length z score at 3 months -6.48), including progressive microcephaly (head circumference z score at 3 months -10.94). Genetic testing revealed novel compound heterozygous XRCC4 variants in trans: c.628A>T and c.638+3A>G. The child ultimately had cardiopulmonary arrest and died at 6 months of life. Molecular diagnosis in MPD is key to defining the natural history, management, and prognosis for patients with these rare disorders.