Midline Facial Defects Research Articles

A BMP-controlled metabolic/epigenetic signaling cascade directs midfacial morphogenesis.

Craniofacial anomalies, especially midline facial defects, are among the most common birth defects in patients and are associated with increased mortality or require lifelong treatment. During mammalian embryogenesis, specific instructions arising at genetic, signaling, and metabolic levels are important for stem cell behaviors and fate determination, but how these functionally relevant mechanisms are coordinated to regulate craniofacial morphogenesis remain unknown. Here, we report that bone morphogenetic protein (BMP) signaling in cranial neural crest cells (CNCCs) is critical for glycolytic lactate production and subsequent epigenetic histone lactylation, thereby dictating craniofacial morphogenesis. Elevated BMP signaling in CNCCs through constitutively activated ACVR1 (ca-ACVR1) suppressed glycolytic activity and blocked lactate production via a p53-dependent process that resulted in severe midline facial defects. By modulating epigenetic remodeling, BMP signaling-dependent lactate generation drove histone lactylation levels to alter essential genes of Pdgfra, thus regulating CNCC behavior in vitro as well as in vivo. These findings define an axis wherein BMP signaling controls a metabolic/epigenetic cascade to direct craniofacial morphogenesis, thus providing a conceptual framework for understanding the interaction between genetic and metabolic cues operative during embryonic development. These findings indicate potential preventive strategies of congenital craniofacial birth defects via modulating metabolic-driven histone lactylation.

THU201 Atypical Presentation Of Kallmann Syndrome With A Rare Genetic Mutation

Abstract Disclosure: E.L. Montgomery: None. B. Thrasher: None. S. Watson: None. Kallmann Syndrome presents as idiopathic hypogonadotropic hypogonadism with additional findings of hyposmia or anosmia and midline facial defects, including cleft lip/palate. We present a case of Kallmann Syndrome due to a rare genetic mutation with absent Mullerian structures. A 15 year, 6 month old female with history of cleft lip and palate and short stature was referred for primary amenorrhea. Clinical history was notable for limited sense of smell and no signs of puberty, including thelarche or adrenarche. Family History unknown (adopted). Significant physical exam findings include tanner 1 breast, no pubic or axillary hair, normal external female genitalia without clitoromegaly, unestrogenized vaginal introitus. Height 147cm (0.88%ile for age). Lab evaluation consisted of: LH 0.66 mIU/ml (2.4-12.6 mIU/ml), FSH 1.63 mIU/ml (3.5-12.5 mIU/ml), prolactin 11.30 ng/ml (4.79-23.30 ng/ml), BhCG negative, testosterone 8 ng/dl (2-17 ng/dl), free testosterone 1.1 pg/ml (<2.2 pg/ml), estradiol 3.0 pg/ml (9.0-249.0 pg/ml), AMH 2.46 ng/ml (1.05-12.86 ng/ml), thyroid function testing and growth factors normal. Imaging included pelvic ultrasound that showed no uterus or gonads. An MRI was obtained that confirmed these findings and also a blind-ending vaginal canal. While the presentation is suggestive of Kallmann Syndrome, the lack of Mullerian structures on imaging has not previously been described. Further evaluation included karyotype (46, XX) and hypogonadotropic hypogonadism genetic panel that identified a mutation in the FGFR1 gene with c.2172C>G (p.Asn724Lys), heterozygous, variant of uncertain significance. Estrogen replacement therapy was initiated with subsequent expected pubertal progression. Repeat imaging after seven months of treatment demonstrated presence of normal developing uterus and bilateral ovaries. Clinical Lesson/Conclusion: 1.Rare mutation with now 3 reports suggesting it is a true pathologic variant2.Unique presentation with hypoplastic Mullerian structures not detected on imaging.This patient’s particular variant has previously been described in in 2 individuals (mother/son) with features of Kallmann Syndrome (PMID: 16606836) with normal and partial puberty respectively, increasing the suspicion that this variant is pathogenic. Newly described FGFR1 variant associated with Kallmann Syndrome / hypogonadotropic hypogonadism. Kallmann Syndrome is not associated with lack of Mullerian structures, however this patient presented with features of Kallmann Syndrome and imaging that did not demonstrate presence of Mullerian structures. Since initiating estrogen therapy, she has had appropriate development of uterus and ovaries. This case demonstrates that prior to estrogen therapy, patients with Kallmann Syndrome may have underdeveloped Mullerian structures that not recognized on imaging prior to estrogen replacement therapy. Presentation: Thursday, June 15, 2023

Congenital hypopituitarism due to novel compound heterozygous POU1F1 gene mutation: A case report and review of the literature

Failure to thrive is one of the most common complaints in the endocrinology and genetics clinic. An 8-month-old girl with presentation of motor developmental delay, failure to thrive, and midline facial defects, with history of hypoglycemia at birth and central congenital hypothyroidism (CCH), was brought to our genetic clinic. Hormone test demonstrated combined pituitary hormone deficiency with growth hormone deficiency (GHD), central hypothyroidism, and hypoprolactinemia. Brain magnetic resonance imaging (MRI) showed anterior pituitary hypoplasia (APH), abnormal pituitary stalk, and preserved posterior pituitary lobe. Whole exome sequence (WES) identified a compound heterozygous mutation of the POU1F1 gene: c.649C>T (p.Arg217Ter) and c.662T>C (p.Ile221Thr), which are de novo mutation and inherited from mother, respectively. The patient's phenotype was consistent clinically with congenital hypopituitarism due to the POU1F1 gene mutation. Based on our literature review, this is the first report of the c.662T>C mutation, to the best of our knowledge. Our study demonstrates the power of WES for early diagnosis of congenital hypopituitarism with its relative phenotype for improving prognosis and preventing irreversible deficit.

Genetics of hypogonadotropic Hypogonadism—Human and mouse genes, inheritance, oligogenicity, and genetic counseling

Hypogonadotropic hypogonadism, which may be normosmic (nHH) or anosmic/hyposmic, known as Kallmann syndrome (KS), is due to gonadotropin-releasing hormone deficiency, which results in absent puberty and infertility. Investigation of the genetic basis of nHH/KS over the past 35 years has yielded a substantial increase in our understanding, as variants in 44 genes in OMIM account for ~50% of cases. The first genes for KS (ANOS1) and nHH (GNRHR) were followed by the discovery that FGFR1 variants may cause either nHH or KS. Associated anomalies include midline facial defects, neurologic deficits, cardiac anomalies, and renal agenesis, among others. Mouse models for all but one gene (ANOS1) generally support findings in humans. About half of the known genes implicated in nHH/KS are inherited as autosomal dominant and half are autosomal recessive, whereas only 7% are X-linked recessive. Digenic and oligogenic inheritance has been reported in 2–20% of patients, most commonly with variants in genes that may result in either nHH or KS inherited in an autosomal dominant fashion. In vitro analyses have only been conducted for both gene variants in eight cases and for one gene variant in 20 cases. Rigorous confirmation that two gene variants in the same individual cause the nHH/KS phenotype is lacking for most. Clinical diagnosis is probably best accomplished by targeted next generation sequencing of the known candidate genes with confirmation by Sanger sequencing. Elucidation of the genetic basis of nHH/KS has resulted in an enhanced understanding of this disorder, as well as normal puberty, which makes genetic diagnosis clinically relevant.

Bilateral Morning Glory Anomaly With Optic Nerve Multiple Cysts

We herein describe a pediatric case of bilateral morning glory anomaly whose retrobulbar cysts and renal disease were underdiagnosed, and finally, he was diagnosed with renal coloboma syndrome. We recommend patients with colobomatous optic nerve malformations undergo a complete workup to avoid missed diagnosis, which includes (i) general physical examination looking for heart defects, genitourinary, auricular, and midline facial defects among other abnormalities; (ii) simple nephrologic investigations such as routine urine test and/or renal ultrasound to check for renal hypoplasia; and (iii) neuroimaging check for cerebrovascular anomalies and midline cranial defects. Genetic testing can be a useful tool to guide the workup.

SECONDARY ADRENAL INSUFFICIENCY MIMICKING ABDOMINAL CAUSE OF RECURRENT ABDOMINAL PAIN IN A PREPUBERTAL GIRL

Recurrent abdominal pain (RAP) in children is defined as at least three episodes of pain that occur over at least three months and affect the child's ability to perform normal activities. The prevalence of recurrent abdominal pain in a population of schoolchildren varies from 10% to even 45%. Pituitary disorders are rarely considered as causative factor in children with abdominal pain, especially in absence of midline facial defects and in case of emergency, when growth monitoring is neglected or not performed carefully. Herein we report an unusual case of RAP caused by secondary adrenal insufficiency. An 8-year-old girl was hospitalized repeatedly because of RAP. Biological parameters including white blood cell count, hemoglobin value, C-reactive protein, glucose, electrolytes were within the normal range. Low cortisol combined with low ACTH values was the clue for diagnosis. The magnetic resonance imaging (MRI) of the pituitary region revealed anterior pituitary hypoplasia and pituitary stalk interruption. To the best of our knowledge, this is the first report of child with RAP caused by pituitary disorder. Possible inherited, autoimmune and post-traumatic causative factors are discussed.

Kallmann syndrome: phenotype and genotype of hypogonadotropic hypogonadism

Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency (IGD) IGD is a genetically and clinically heterogeneous disorder. Mutations in many different genes are able to explain ~40% of the causes of IGD, with the rest of cases remaining genetically uncharacterized. While most mutations are inherited in X-linked, autosomal dominant, or autosomal recessive pattern, several IGD genes are shown to interact with each other in an oligogenic manner. In addition, while the genes involved in the pathogenesis of IGD act on either neurodevelopmental or neuroendocrine pathways, a subset of genes are involved in both pathways, acting as “overlap genes”. Thus, some IGD genes play the role of the modifier genes or “second hits”, providing an explanation for incomplete penetrance and variable expressivity associated with some IGD mutations.The clinical spectrum of IGD includes a variety of disorders including Kallmann Syndrome (KS), i.e. hypogonadotropic hypogonadism with anosmia, and its normosmic variation normosmic idiopathic hypogonadotropic hypogonadism (nIHH), which represent the most severe aspects of the disorder. Apart from these disorders, there are also “milder” and more common reproductive diseases associated with IGD, including hypothalamic amenorrhea (HA), constitutional delay of puberty (CDP) and adult-onset hypogonadotropic hypogonadism (AHH). Interestingly, neurodeveloplmental genes are associated with the KS form of IGD, due to the topographical link between the GnRH neurons and the olfactory placode. On the other hand, neuroendocrine genes are mostly linked to nIHH. However, a great deal of clinical and genetic overlap characterizes the spectrum of the IGD disorders. IGD is also characterized by a wide variety of non-reproductive features, including midline facial defects such as cleft lip and/or palate, renal agenesis, short metacarpals and other bone abnormalities, hearing loss, synkinesia, eye movement abnormalities, poor balance due to cerebellar ataxia, etc. Therefore, genetic screening should be offered in patients with IGD, as it can provide valuable information for genetic counseling and further understanding of IGD.

Midline Facial Defects With Associated Brain Anomaly

Midline Facial Defects With Associated Brain Anomaly

Ethmocephaly: A rare cephalic disorder.

Dear Sir, A male neonate, product of nonconsanguineous marriage, was delivered vaginally with severe birth asphyxia (Apgar score 3, 4, 6) to a primiparous woman at 36 weeks’ gestation. The mother did not have any medical illness during pregnancy, and an antenatal ultrasound was performed at 29 weeks’ gestation which revealed holoprosencephaly with midline facial defect in the fetus. Examination after birth revealed weight of 2.6 kg, head circumference 31 cm (<3rd centile), facial dysmorphism (bilateral cleft lip, incomplete cleft palate, a central proboscis with a single nare, hypoplastic eyeballs, low-set ears), short neck with low hairline, widely spaced nipples, sandal gap in both feet, and bilateral simian crease [Figure 1]. He also had a large anterior fontanelle with widely separated sutures. The neonate received resuscitation at birth and was shifted to neonatal intensive care unit. He was put on mechanical ventilation and supportive therapy. Ultrasound of the head revealed undivided cerebral hemispheres with a single ventricle. Our neonate expired at 12 h of life following cardiorespiratory arrest. Karyotyping was performed which was reported as normal. Figure 1 Neonate with bilateral cleft lip, cleft palate, and a central proboscis with single nare and low set ears Ethmocephaly is the rarest phenotypic variant of a group of defects called the holoprosencephaly (HPE) malformation sequence;[1] other variants include cebocephaly, cyclopia, and median cleft palate. HPE is a cephalic disorder characterized by congenital brain malformation due to incomplete cleavage of the prosencephalon occurring between the 18th and 28th day of gestation. HPE is categorized into three levels of increasing severity: Lobar (where the right and left ventricles are separated, but with some continuity across the frontal cortex); semilobar (partial separation of hemispheres), and the most severe form alobar HPE (single brain ventricle and no interhemispheric fissure).[2] HPE can be caused by both genetic and environmental factors such as maternal insulin-dependent diabetes mellitus (1% risk of HPE),[3] maternal alcoholism, prenatal exposure to teratogens (alcohol, retinoic acid, cholesterol biosynthesis inhibitors, and maternal infections (cytomegalovirus, toxoplasmosis, rubella).[4] Some genetic associations with trisomy 13 or 18 have been reported.[5] Multiple malformation syndromes such as Kallmann syndrome, Pallister–Hall, Smith–Lemli–Opitz, and CHARGE syndrome have been found to be associated with HPE. However, nearly 70% cases are sporadic. Nearly all HPE malformation disorders have a fatal outcome during gestation or in early infancy. HPE can be detected by ultrasonography in the first trimester. Ultrasonographic markers include hypertelorism and a single common cerebral ventricle with absent midline echo. Other investigations include chromosomal analysis by karyotyping and genetic mutation analysis by denaturing high-performance liquid chromatography and multiplex polymerase chain reaction. Ethmocephaly is a rare cephalic disorder with a reported incidence of 1 in 15,000 among live births and 1 in 250 among abortuses.[1] It characterized by HPE with an undivided cerebrum and a single ventricle. In addition, there is a midline facial anomaly associated with a central proboscis, two well-formed orbits with absent or hypoplastic eyeballs, hypotelorism, and low set ears. It is differentiated from other HPE disorders namely cyclopia where the two eyes are fused together in a single median orbit and from cebocephaly which is characterized by a flattened nose with single nostril located below close-set eyes, based on the phenotype. Our case presented with midline facial defects, hypotelorism, bilateral microphthalmos, a central proboscis and bilateral low set ears, and alobar HPE, which are characteristic of ethmocephaly. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

Alobar holoprosencephaly: A case report

Holoprosencephaly (HPE) is a rare congenital brain malformation associated with multiple midline facial defects. This anomaly is resulted from the failure of diverticulation and cleavage of primitive prosencephalon during weeks 4-8 of gestation. HPE is the most common forebrain developmental anomaly in human with the incidence rate of 0.49-1.2 cases per 10,000-20,000 term births. In this study, we described a case of HPE in a neonate with gestational age of 32 weeks. Antenatal ultrasonographic diagnosis was performed, and the infant was presented with macrocephaly, bilateral microphthalmia, hypotelorism, proboscis and ambiguous genitalia.

Holoprosencephaly: signaling interactions between the brain and the face, the environment and the genes, and the phenotypic variability in animal models and humans

Holoprosencephaly (HPE) is the most common developmental defect of the forebrain characterized by inadequate or absent midline division of the forebrain into cerebral hemispheres, with concomitant midline facial defects in the majority of cases. Understanding the pathogenesis of HPE requires knowledge of the relationship between the developing brain and the facial structures during embryogenesis. A number of signaling pathways control and coordinate the development of the brain and face, including Sonic hedgehog, Bone morphogenetic protein, Fibroblast growth factor, and Nodal signaling. Mutations in these pathways have been identified in animal models of HPE and human patients. Because of incomplete penetrance and variable expressivity of HPE, patients carrying defined mutations may not manifest the disease at all, or have a spectrum of defects. It is currently unknown what drives manifestation of HPE in genetically at-risk individuals, but it has been speculated that other gene mutations and environmental factors may combine as cumulative insults. HPE can be diagnosed in utero by a high-resolution prenatal ultrasound or a fetal magnetic resonance imaging, sometimes in combination with molecular testing from chorionic villi or amniotic fluid sampling. Currently, there are no effective preventive methods for HPE. Better understanding of the mechanisms of gene-environment interactions in HPE would provide avenues for such interventions.

Impact of retinoic acid exposure on midfacial shape variation and manifestation of holoprosencephaly in Twsg1 mutant mice.

Holoprosencephaly (HPE) is a developmental anomaly characterized by inadequate or absent midline division of the embryonic forebrain and midline facial defects. It is believed that interactions between genes and the environment play a role in the widely variable penetrance and expressivity of HPE, although direct investigation of such effects has been limited. The goal of this study was to examine whether mice carrying a mutation in a gene encoding the bone morphogenetic protein (BMP) antagonist twisted gastrulation (Twsg1), which is associated with a low penetrance of HPE, are sensitized to retinoic acid (RA) teratogenesis. Pregnant Twsg1+/− dams were treated by gavage with a low dose of all-trans RA (3.75 mg/kg of body weight). Embryos were analyzed between embryonic day (E)9.5 and E11.5 by microscopy and geometric morphometric analysis by micro-computed tomography. P19 embryonal carcinoma cells were used to examine potential mechanisms mediating the combined effects of increased BMP and retinoid signaling. Although only 7% of wild-type embryos exposed to RA showed overt HPE or neural tube defects (NTDs), 100% of Twsg1−/− mutants exposed to RA manifested severe HPE compared to 17% without RA. Remarkably, up to 30% of Twsg1+/− mutants also showed HPE (23%) or NTDs (7%). The majority of shape variation among Twsg1+/− mutants was associated with narrowing of the midface. In P19 cells, RA induced the expression of Bmp2, acted in concert with BMP2 to increase p53 expression, caspase activation and oxidative stress. This study provides direct evidence for modifying effects of the environment in a genetic mouse model carrying a predisposing mutation for HPE in the Twsg1 gene. Further study of the mechanisms underlying these gene-environment interactions in vivo will contribute to better understanding of the pathogenesis of birth defects and present an opportunity to explore potential preventive interventions.

Maternal Diet Supplementation with Methyl Donors and Increased Parity Affect the Incidence of Craniofacial Defects in the Offspring of Twisted gastrulation Mutant Mice

Diets rich in methyl-donating compounds, including folate, can provide protection against neural tube defects, but their role in preventing craniofacial defects is less clear. Mice deficient in Twisted gastrulation (TWSG1), an extracellular modulator of bone morphogenetic protein signaling, manifest both midline facial defects and jaw defects, allowing study of the effects of methyl donors on various craniofacial defects in an experimentally tractable animal model. The goal of this study was to examine the effects of maternal dietary supplementation with methyl donors on the incidence and type of craniofacial defects among Twsg1−/− offspring. Nulliparous and primiparous female mice were fed an NIH31 standard diet (control) or a methyl donor supplemented (MDS) diet (folate, vitamin B-12, betaine, and choline). Observed defects in the pups were divided into those derived mostly from the first branchial arch (BA1) (micrognathia, agnathia, cleft palate) and midline facial defects in the holoprosencephaly spectrum (cyclopia, proboscis, and anterior truncation). In the first pregnancy, offspring of mice fed the MDS diet had lower incidence of BA1-derived defects (12.8% in MDS vs. 32.5% in control; P = 0.02) but similar incidence of midline facial defects (6.4% in MDS vs. 5.2% in control; P = 1.0). Increased maternal parity was independently associated with increased incidence of craniofacial defects after adjusting for diet (from 37.7 to 59.5% in control, P = 0.04 and from 19.1 to 45.3% in MDS, P = 0.045). In conclusion, methyl donor supplementation shows protective effects against jaw defects, but not midline facial defects, and increased parity can be a risk factor for some craniofacial defects.

A familial case with interstitial 2q36 deletion: Variable phenotypic expression in full and mosaic state

Submicroscopic chromosomal anomalies play an important role in the etiology of craniofacial malformations, including midline facial defects with hypertelorism (MFDH). MFDH is a common feature combination in several conditions, of which Frontonasal Dysplasia is the most frequently encountered manifestation; in most cases the etiology remains unknown. We identified a parent to child transmission of a 6.2 Mb interstitial deletion of chromosome region 2q36.1q36.3 by array-CGH and confirmed by FISH and microsatellite analysis. The patient and her mother both presented an MFDH phenotype although the phenotype in the mother was much milder than her daughter. Inspection of haplotype segregation within the family of 2q36.1 region suggests that the deletion arose on a chromosome derived from the maternal grandfather. Evidences based on FISH, microsatellite and array-CGH analysis point to a high frequency mosaicism for presence of a deleted region 2q36 occurring in blood of the mother. The frequency of mosaicism in other tissues could not be determined. We here suggest that the milder phenotype observed in the proband's mother can be explained by the mosaic state of the deletion. This most likely arose by an early embryonic deletion in the maternal embryo resulting in both gonadal and somatic mosaicism of two cell lines, with and without the deleted chromosome. The occurrence of gonadal mosaicism increases the recurrence risk significantly and is often either underestimated or not even taken into account in genetic counseling where new mutation is suspected.

Novel Heterozygous Nonsense GLI2 Mutations in Patients with Hypopituitarism and Ectopic Posterior Pituitary Lobe without Holoprosencephaly

GLI2 is a transcription factor downstream in Sonic Hedgehog signaling, acting early in ventral forebrain and pituitary development. GLI2 mutations were reported in patients with holoprosencephaly (HPE) and pituitary abnormalities. The aim was to report three novel frameshift/nonsense GLI2 mutations and the phenotypic variability in the three families. The study was conducted at a university hospital. The GLI2 coding region of patients with isolated GH deficiency (IGHD) or combined pituitary hormone deficiency was amplified by PCR using intronic primers and sequenced. Three novel heterozygous GLI2 mutations were identified: c.2362_2368del p.L788fsX794 (family 1), c.2081_2084del p.L694fsX722 (family 2), and c.1138 G>T p.E380X (family 3). All predict a truncated protein with loss of the C-terminal activator domain. The index case of family 1 had polydactyly, hypoglycemia, and seizures, and GH, TSH, prolactin, ACTH, LH, and FSH deficiencies. Her mother and seven relatives harboring the same mutation had polydactyly, including two uncles with IGHD and one cousin with GH, TSH, LH, and FSH deficiencies. In family 2, a boy had cryptorchidism, cleft lip and palate, and GH deficiency. In family 3, a girl had hypoglycemia, seizures, excessive thirst and polyuria, and GH, ACTH, TSH, and antidiuretic hormone deficiencies. Magnetic resonance imaging of four patients with GLI2 mutations and hypopituitarism showed a hypoplastic anterior pituitary and an ectopic posterior pituitary lobe without HPE. We describe three novel heterozygous frameshift or nonsense GLI2 mutations, predicting truncated proteins lacking the activator domain, associated with IGHD or combined pituitary hormone deficiency and ectopic posterior pituitary lobe without HPE. These phenotypes support partial penetrance, variable polydactyly, midline facial defects, and pituitary hormone deficiencies, including diabetes insipidus, conferred by heterozygous frameshift or nonsense GLI2 mutations.

Malformations of Cortical Development in Patients with Midline Facial Defects and Ocular Hypertelorism

We studied the neuroimaging and neurophysiological aspects of 17 patients with midline facial defects with ocular hypertelorism (MFDH). The investigation protocol included a previous semistructured questionnaire about family history; gestational, neonatal, and postnatal development; and dysmorphologic and neurologic evaluation. Recognized monogenic disorders and individuals with other well-known conditions were excluded. All patients had high resolution magnetic resonance imaging (MRI) with multiplanar reconstruction (MPR) and routine electroencephalograms (EEGs). We detected abnormalities in five patients whose MRIs had been previously reported as normal. MRI showed central nervous system (CNS) structural abnormalities in all patients, which included commissural alterations in 16/17 (94%), malformations of cortical development in 10/17 (58%), disturbances of neural tube closure in 7/17 (42%), and posterior fossa anomalies in 6/17 (35%). Some patients had more than one type of malformation occurring at different stages of the embryonary process. EEGs showed epileptiform activity in 4/17 (24%) and background abnormalities in 5/17 (29%) of patients. This study clearly demonstrated the presence of structural and functional neurologic alterations related to MFDH. Therefore, the CNS anomalies cannot be considered incidental findings but an intrinsic part of this condition, which could be related to environmental effects and/or genetic mutations. These findings would provide a basis for future investigations on MFDH and should also be considered when planning rehabilitation.

Investigation of the 22q11.2 candidate region in patients with midline facial defects with hypertelorism

Midline facial defects with hypertelorism (MFDH) are mainly characterized by ocular hypertelorism and bifid nose. They are often associated with structural and functional anomalies of the central nervous system similar to those found in 22q11.2 deletion syndromes. In addition, there are some isolated reports of MFDH and 22q11.2 deletion. These findings suggest that MFDH may be part of the spectrum of 22q11.2 deletion syndromes. To test this hypothesis, 10 individuals with MFDH were analyzed by fluorescent in situ hybridization (FISH), but no 22q11.2 deletion was detected. In view of this result, the TBX1 gene located within the 22q11.2 candidate region was screened. A new sequence variant (1132GA) was identified in one patient. This variant was not found in 110 control individuals genotyped. Considering the rarity of this condition and results of this study, the involvement of the 22q11.2 chromosomal region in the pathogenesis of MFDH could not be excluded.

Malformations of cortical development in patients with midline facial defects and ocular hypertelorism

Malformations of cortical development in patients with midline facial defects and ocular hypertelorism

Holoprosencephaly and Diabetes Insipidus in a 3-Month-Old Infant

Holoprosencephaly is a developmental defect caused by incomplete cleavage of the embryonic forebrain structures during early embryogenesis. We describe a 3-month-old boy with median cleft palate, surgically reconstructed cleft lip, hypotelorism with a flat nose, cryptorchidism, clubfoot, and microcephaly. During the laboratory investigation, his blood sodium level was 154 mmol/L and urine specific gravity was 1.007. Serum osmolarity was 317 mOsm/kg and urine osmolarity was 268 mOsm/kg. Given these findings and the clinical response to vasopressin, diagnosis of central diabetes insipidus was made. Magnetic resonance imaging revealed semilobar holoprosencephaly. The patient responded very well to vasopressin treatment with restoration of serum electrolytes, which remained within normal limits on follow-up. In case of midline facial defects accompanied by hypotelorism with or without developmental delay, the brain should be imaged to confirm its morphology and investigations should be directed by a high index of suspicion of associated endocrinologic dysfunctions.

A clinical study of 31 individuals with midline facial defects with hypertelorism and a guideline for follow-up

In order to contribute to clinical delineation of midline facial defects with hypertelorism (MFDH) and to etiologic diagnosis of the isolated form, 31 patients with MFDH unaffected by known syndromic associations were evaluated. Group A included patients personally examined by the authors, while Group B included those previously evaluated by other geneticists. Among the 14 patients from Group A, there were 7 with distinct pictures of multiple congenital anomalies. In Group B, 5 of the 17 patients also exhibited a distinct pattern of defects. Among isolated MFDH, there was association with anomalies of the skull and facial bones (13/14), otorhinologic (11/16), central nervous system (9/16), and ocular (6/7), and audiologic (3/16); 1/3 of the cases had a relevant gestational intercurrences. Isolated FNM may have involvement of environmental components in some cases; the possibility of a syndromic picture should be extensive investigated. Follow-up of such patients must include the examinations herein performed.