Hypoplastic External Genitalia Research Articles

HNRNPR Variants that Impair Homeobox Gene Expression Drive Developmental Disorders in Humans

The heterogeneous nuclear ribonucleoprotein (HNRNP) genes code for a set of RNA-binding proteins that function primarily in the spliceosome C complex. Pathogenic variants in these genes can drive neurodegeneration, through a mechanism involving excessive stress-granule formation, or developmental defects, through mechanisms that are not known. Here, we report four unrelated individuals who have truncating or missense variants in the same C-terminal region of hnRNPR and who have multisystem developmental defects including abnormalities of the brain and skeleton, dysmorphic facies, brachydactyly, seizures, and hypoplastic external genitalia. We further identified in the literature a fifth individual with a truncating variant. RNA sequencing of primary fibroblasts reveals that these HNRNPR variants drive significant changes in the expression of several homeobox genes, as well as other transcription factors, such as LHX9, TBX1, and multiple HOX genes, that are considered fundamental regulators of embryonic and gonad development. Higher levels of retained intronic HOX sequences and lost splicing events in the HOX cluster are observed in cells carrying HNRNPR variants, suggesting that impaired splicing is at least partially driving HOX deregulation. At basal levels, stress-granule formation appears normal in primary and transfected cells expressing HNRNPR variants. However, these cells reveal profound recovery defects, where stress granules fail to disassemble properly, after exposure to oxidative stress. This study establishes an essential role for HNRNPR in human development and points to a mechanism that may unify other "spliceosomopathies" linked to variants that drive multi-system congenital defects and are found in hnRNPs.

Achieving Full Anatomical Correction in Girls with cloacal anomalies: A Necessity or an Overdoing?

Purpose: To highlight a different concept for the urogenitoplasty in the management of cloaca and its possible implications on functional and cosmetic outcome.Patients and Methods: The study included six cases of cloaca who were recently managed during the period 2011 through 2015. Regarding urogenitoplasty, two cases with low urogenital confluence had a short common channel and were managed by introitoplasty in one and partial urogenital sinus mobilization in the other. One case with high distended vagina communicating close to the bladder neck was managed by vaginal pull-through, while keeping the common urogenital sinus to act as urethra. In between, three intermediate cases were also managed by introitoplasty, while keeping them with the common urogenital sinus uncorrected.Results: The follow-up period ranged from 2 to 6.5 years. Apart from the hypoplastic external genitalia, all cases included in the study had minimal perineal scaring compared with old cases that underwent extensive perineal ‘urogenital’ dissection. Urinary and stool incontinence was observed in one case that was associated with caudal regression syndrome. Another case that underwent vaginal pull-through had poor evacuation of the urinary bladder; this was managed by anticholinergics and clean intermittent catheterization. The rest of cases had voluntary bowel movements and spontaneous voluntary micturition.Conclusion: Considering the potential risk and complications of separating the vagina from the urethra in some cases of cloaca, it might be better from the functional and cosmetic point of view to perform just introitoplasty while keeping these girls with the common urogenital sinus uncorrected.

De novo WNT5A‐associated autosomal dominant Robinow syndrome suggests specificity of genotype and phenotype

Robinow Syndrome (RS), a rare skeletal dysplasia syndrome, is characterized by dysmorphic features resembling a fetal face, mesomelic limb shortening, hypoplastic external genitalia in males, and renal and vertebral anomalies. Both autosomal dominant and autosomal recessive patterns of inheritance have been reported. Since the description of autosomal dominant Robinow Syndrome (ADRS; OMIM 180700) in 1969 by Meinhard Robinow and colleagues, the molecular etiology remained elusive until only recently. WNT5A was proposed to be the candidate gene for ADRS, as mutations were found in two affected families, one of those being the originally described index family. We report three families with RS caused by novel heterozygous WNT5A mutations, which were confirmed in the first family by whole exome sequencing, and in all by Sanger sequencing. To our knowledge, this is the largest number of published families with ADRS in whom a WNT5A mutation was identified. Families 1 and 2 are the first cases showing de novo inheritance in the affected family members and thus strengthen the evidence for WNT5A as the causative gene in ADRS. Finally, we propose WNT5A mutation specificity in ADRS, which may affect interactions with other proteins in the Wnt pathway.

Atypical pulmonary carcinoid tumour in a 28-year-old nonsmoker with Prader-Willi syndrome

To the Editors: In recent years, the life expectancy of patients with Prader–Willi syndrome (PWS) has increased, unveiling several cases of early-onset cancer and raising the question whether the condition predisposes to tumourigenesis. We encountered a unique occurrence of pulmonary atypical carcinoid in a young never-smoker with PWS. A 28-yr-old, morbidly obese male with PWS was admitted as a candidate for gastric bypass. He was a lifetime nonsmoker, and his height, weight and body mass index were 1.78 m, 175 kg, and 55.2 kg·m−2, respectively. Polyphagia, obesity and a failure to achieve psychosocial milestones became apparent at the age of 5 yrs, when PWS was diagnosed based on clinical findings and a de novo deletion of the proximal region of chromosome 15 (del(15)(q11–q13)). Type II diabetes mellitus was diagnosed at the age of 17 yrs, and dietary control along with administration of sulfonylurea was initiated. The remainder of the anamnesis included low levels of testosterone, which were treated with monthly intramuscular depot injections of testosterone enanthate (250 mg). On admission, the patient reported mild shortness of breath, nonproductive cough and malaise of indeterminate origin. A physical exam revealed markedly increased subcutaneous fat, picking scars, hypoplastic external genitalia and a polyphonic wheeze over the right hemithorax. Pulse was regular and of normal rate, diastolic blood pressure was elevated (98 mmHg) and haemoglobin oxygen saturation was 96% in room air. Electrocardiography was normal. Laboratory data, including blood cell counts, routine serum biochemistry and coagulation times, were within normal limits, except for fasting plasma glucose (178 mg·dL−1) and lipids (total cholesterol 233 mg·dL−1; high-density lipoprotein cholesterol 32 mg·dL−1; triglycerides 322 mg·dL−1). A pre-operative chest radiograph, performed routinely but also prompted by the patient’s wheeze, showed a round, regular-shaped opacity of soft-tissue quality measuring …

De novo duplication of Xq22.1→q24 with a disruption of the NXF gene cluster in a mentally retarded woman with short stature and premature ovarian failure

Objective To present molecular cytogenetic characterization of a de novo duplication of Xq22.1→q24 in a mentally retarded woman with short stature and premature ovarian failure. Materials and Methods A 19-year-old woman presented with psychomotor retardation, developmental delay, mental retardation, short stature, low body weight, general muscle hypotonia, distal muscle hypotrophy of the lower extremities, elongated digits, scanty pubic and axillary hair, hypoplastic external female genitalia, and secondary amenorrhea but no clinical features of Pelizaeus-Merzbacher disease. Conventional cytogenetic analysis revealed a karyotype of 46,X,dup(X)(q22.1q24). Fluorescence in situ hybridization determined a direct duplication with a linear tandem orientation. Array comparative genomic hybridization demonstrated partial trisomy Xq [arr cgh Xq22.1q24 (101,490,234–119,070,188 bp)×3] with a 17.6-Mb duplication. Results The duplicated region contained NXF2B, NXF4, NXF3, PLP1, and PGRMC1 genes. There was a disruption of the NXF gene cluster of Xcen- NXF5- NXF2- NXF2B- NXF4- NXF3-Xqter. Conclusion A duplication of Xq22.1→q24 with a disruption of the NXF gene cluster in female patients can be associated with clinical manifestations of mental retardation in addition to short stature and premature ovarian failure.

Hay–Wells syndrome (AEC): a case report

We would like to present a case of the rare genetic skin disorder catalogued as AEC syndrome. This rare disorder was described in 1976 by Hay and Wells in seven individuals from four families, and it entails a complex polymalformative syndrome with an autosomal-dominant inheritance pattern and variable penetration. Descriptive explanation and facial and intraoral images of this rare disorder constituted the study design. The neonatal report outlines dysplastic phenotype, micrognathia, hypoplasia of the hard and soft palate, cleft palate, small nose, mammary hypoplasia with ectopic mammary nodules, hypoplastic external genitalia with clitoral hypertrophy, hypoplasia of the nails, a tendency towards dorsiflexion of the big toe on both feet, ankyloblepharon filiforme, low positioning of the auricles and faulty development of the left auricle, scaly exanthema with eritrodermatitis and hyperkeratosis, good lung ventilation, normal heart rhythm and normal neurological examination. Although only a few cases published are available, clinical variability is one of the hallmarks of AEC syndrome. The majority of authors consider ankyloblepharon, ectodermal dysplasia and orofacial clefting as cardinal signs. They are all are present in the case reported.

Midline cleft of the lower lip associated with Robinow syndrome

Robinow syndrome (also named "fetal face syndrome") includes a series of anomalies including mesomelic brachymelia, bifid terminal phalanges of the hands and feet, abnormalities of vertebrae and ribs, and hypoplastic external genitalia. A midline cleft of the lower lip and mandible is an extremely rare maxillofacial deformity. Seventy cases have so far been described to our knowledge. We report a patient with Robinow syndrome and midline cleft of the lower lip and mandible and describe the reconstruction of these anomalies. We propose that this anomaly should be added to the range of malformations associated with the syndrome.

A Tetraploid Liveborn Neonate: Cytogenetic and Autopsy Findings

Cytogenetic and autopsy findings of a nonmosaic tetraploid male neonate, alive until shortly after birth at 37 weeks' gestation, are described. Oligohydramnios, intrauterine growth retardation, cranial abnormalities, and Dandy-Walker malformation were noted prenatally. Autopsy findings included cleft lip and palate; overlapping fingers; low-set ears; simian creases; hypoplastic external genitalia with undescended testes; Dandy-Walker malformation; slightly dilated lateral and third ventricles; hypoplasia of the cerebrum, pons, medulla, pituitary gland, thymus, lung, adrenal gland, and kidney; large ventricular septal defect; and enteric cyst behind the urinary bladder. The placenta was hypoplastic and showed no remarkable abnormalities, except for mild syncytial knots. Chromosome analyses of amniotic fluid cells at 31 weeks' gestation and the umbilical cord blood cells at delivery revealed a 92,XXYY karyotype. G-, C-, Q-, and N-banding heteromorphic studies demonstrated duplication of paternal chromosomes 1, 3, and 15, and maternal chromosome 22. In addition, the results of an analysis with 16 CA repeat polymorphic markers were consistent with duplicated inheritance of 1 paternal and 1 maternal haploid sets to the tetraploid patient. Therefore, it is most likely that the tetraploidy was caused by a cytoplasmic cleavage failure at the first mitotic division.

Evidence for the ?midline? hypothesis in associated defects of laterality formation and multiple midline anomalies

A male infant was liveborn at 38 weeks of gestation to a G4P1AB2, 22-year-old, mother. Polyhydramnios and multiple congenital anomalies were noted by ultrasonography; the infant died 5 min after birth. At autopsy, the infant had multiple defects of blastogenesis including midline anomalies with asplenia and abnormalities of laterality formation. The laterality defects were unusual in that they combined asplenia with hypoplastic, symmetrically unilobate lungs and bilateral hyparterial bronchi more consistent with polysplenia, abdominal situs inversus with midline stomach, symmetric liver, and left gallbladder. No intracardiac abnormalities were present, but there was azygous continuation of the inferior vena cava. Additional multiple midline defects included bronchoesophageal fistula, duodenal atresia, absence of posterior leaf of diaphragm; horseshoe adrenal gland; microcephaly; Dandy-Walker anomaly with agenesis of cerebellar vermis and occipital encephalocele; holoprosencephaly with orbital encephalocele, midline defect of the orbital plate of the skull, bilateral anophthalmia, double proboscis with bilateral choanal atresia, midline upper lip and palatal cleft; single-lobed thyroid; hypoplastic external genitalia with midline cleft of scrotum, long tapering fingers, and defects of the cranium at the sites of orbital and occipital encephaloceles. Defects of laterality frequently are associated with other complex midline anomalies, which both result from a disturbance of pattern formation during blastogenesis, i.e., the induction of the progenitor fields. The latter are the result of the establishment of upstream expression domains of growth and transcription factors and other morphogens. Many of these and other genetic systems, expressed asymmetrically around the midline, are responsible for laterality formation and are the result of upstream and subsequent downstream gene expression cascades through the expression of genes such as HOX genes; bFGF; transforming growth factor beta/activins/BMP4; WNT-1,8; and SHH.

Hypoplastic external genitalia in association with X;autosome chromosome translocation

Study Objective: To learn the relationship between X;autosome chromosome translocation and hypoplastic external genitalia. Background: An X;autosome translocation usually presents with phenotypic features similar to Turner syndrome. Participants: We present three female siblings and their mother with X;autosome translocation and hypoplastic external genitalia. Methods: Case presentation. Results: Three female siblings, ages 14, 16, and 18 years, presented for routine checkup. All had been seen in the past for short stature, learning disability, and other features similar to those seen in Turner syndrome. At time of presentation, all three had primary amenorrhea. On genital exam, each was found to have hypoplastic external genitalia with absent clitoris and labia minora. Pelvic ultrasound in all subjects showed normal but prepubertal uterus and ovaries. Two subjects have unbalanced translocations with karyotype 46,X,der(9)t(9;X)(q11.2;q22.3). This abnormal chromosome complement results in the loss of the short arm of the X chromosome and the gain of an extra copy of the long arm of chromosome 9. The third subject and her mother have balanced translocations with the karyotype 46,X,t(9;X)(q11.2;q22.3). Xinactivation studies showed skewed inactivation of the normal X chromosome in the balanced translocation carriers, while the two girls with the unbalanced karyotype had skewed inactivation of the translocation product. All subjects have growth hormone deficiency. The oldest sibling was able to menstruate regularly after estrogen/progesterone therapy. The other two patients are currently receiving growth hormone and are gaining height. Conclusion: X;autosome translocations may be associated with hypoplastic external genitalia but normal internal genitalia. Balanced carriers can be fertile. To our knowledge, the presence of hypoplastic external genitalia in association with X;autosome translocation has not been previously reported. This should be added to the possible causes of hypoplastic external genitalia.

Lethal neonatal Hutchinson-Gilford progeria syndrome

We report on a 35-week gestation female fetus with Hutchinson-Gilford progeria (HGP). This patient, who is the first reported with neonatal HGP in the English literature but is the fourth, counting three previous French cases, supports the existence of a more severe prenatal form of progeria. She died 7 hours after birth and presented with intrauterine growth retardation, premature aging, absence of subcutaneous fat, brachydactyly, absent nipples, hypoplastic external genitalia, and abnormal ear lobes. The child's combination of clinical and skeletal manifestations differentiates this form of HGP from other progeroid syndromes with neonatal presentation. We also report previously undescribed autopsy findings including premature loss of hair follicles, premature regression of the renal nephrogenic layer, and premature closure of the growth plates in the distal phalanges that may be related to the aging processes in this condition. We could not find any histological data to support acro-osteolysis, which is the radiographic sign of brachydactyly. The terminal phalanges in HGP seem to be underdeveloped rather than osteolytic.

Lethal neonatal Hutchinson‐Gilford progeria syndrome

We report on a 35-week gestation female fetus with Hutchinson-Gilford progeria (HGP). This patient, who is the first reported with neonatal HGP in the English literature but is the fourth, counting three previous French cases, supports the existence of a more severe prenatal form of progeria. She died 7 hours after birth and presented with intrauterine growth retardation, premature aging, absence of subcutaneous fat, brachydactyly, absent nipples, hypoplastic external genitalia, and abnormal ear lobes. The child's combination of clinical and skeletal manifestations differentiates this form of HGP from other progeroid syndromes with neonatal presentation. We also report previously undescribed autopsy findings including premature loss of hair follicles, premature regression of the renal nephrogenic layer, and premature closure of the growth plates in the distal phalanges that may be related to the aging processes in this condition. We could not find any histological data to support acro-osteolysis, which is the radiographic sign of brachydactyly. The terminal phalanges in HGP seem to be underdeveloped rather than osteolytic. Am. J. Med. Genet. 82:242–248, 1999. © 1999 Wiley-Liss, Inc.

Hypoplastic External Genitalia in Association with X;Autosome Chromosome Trans Location.

<h3>Background</h3> X; autosome translocation usually presents with phenotypic features similar to Turner syndrome. We present three female siblings with X;autosome translocation and hypoplastic external genitalia. <h3>Methods</h3> Case presentation. <h3>Results</h3> Three female siblings, ages 14, 16, and 18 years, presented for routine check up. All had been seen in the past for short stature, primary amenorrhea, and other features similar to those seen in Turner syndrome. On genital exam, each was found to have hypoplastic external genitalia with absent clitoris and labia minora. Pelvic ultrasound in all subjects shows normal but prepubertal uterus and ovaries. Two subjects have unbalanced translocations with karyotype 46.X, der(9)t(9;X)(q11.2;q22.3). This abnormal chromosome complement results in the loss of the short arm of the X chromosome and the gain of an extra copy of the long arm of chromosome 9. The third subject and her mother have balanced translocations with the karyotype 46, X.t (9;X)(qI1.2;q22.3). X-inactivation studies show skewed inactivation of the normal X chromosome, while the two girls with the unbalanced karyotype had skewed inactivation of the translocation product. All subjects have growth hormone deficiency. The two older siblings were able to gain height and to menstruate regularly after growth hormone and estrogen/progesterone therapy. The youngest patient is still receiving growth hormone. <h3>Conclusion</h3> X;autosome translocations may be associated with hypoplastic external genitalia but normal internal genitalia. Balanced carriers can be fertile. To our knowledge. the presence of hypoplastic external genitalia in association with a X;autosome translocation has not been previously reported. This should be added to the possible causes of hypoplastic external genitalia.

Hypogonadism and endocrine metabolic disorders in Prader-Willi syndrome.

Disturbances of the hypothalamic-pituitary-gonadal axis are reviewed in patients with Prader-Willi syndrome, and a brief account is given of thyroid function, adrenal function and glucose metabolism in such patients. Cryptorchidism, hypoplastic external genitalia and delayed or incomplete pubertal development in most patients with Prader-Willi syndrome suggest dysfunction of the hypothalamic-pituitary-gonadal axis. Decreased levels of gonadotrophins, consistent with hypogonadotrophic hypogonadism, have been found in some patients, whereas others appear to have hypergonadotrophic hypogonadism secondary to cryptorchidism and its treatment. Gonadal function is normal in a small number of patients with the syndrome. Although most clinicians agree that cryptorchidism should be corrected in early childhood, in practice the surgery is often not performed. In addition, most patients do not receive sex hormone replacement therapy. It is therefore suggested that more aggressive endocrine treatment strategies for hypogonadism are warranted in both children and adults with Prader-Willi syndrome. Both thyroid function and adrenal function appear to be normal in most patients, and glucose metabolism is similar to that in normal obese individuals.

Redefining the Genital Abnormality in the Robinow Syndrome

Purpose We defined the anatomical structure of the male genital abnormality in the Robinow syndrome. Features of this syndrome include mesomelic brachymelia of the arms, bifid terminal phalanges of the hands and feet, characteristic facies, skeletal anomalies and hypoplastic external genitalia. Materials and Methods Penile anatomy of 3 patients with the Robinow syndrome was assessed using computerized tomography and magnetic resonance imaging. Results were compared to those of 4 controls who underwent imaging for pelvic malignancies. Results Cross-sectional imaging showed that normal penile crura were inserted onto the anteromedial aspect of the pubic bone. In contrast, in the Robinow syndrome they were inserted inferiorly and posteriorly onto the medial aspect of the ischial tuberosity. In addition, the crura in the Robinow syndrome extended posterior to a line intersecting both femoral shafts. Compared to controls, there was a significant gap between the symphysis pubis and dorsal aspect of the penis. Conclusions The penile anomaly in the Robinow syndrome is due to abnormal insertion of the penile crura, resulting in a penis that appears shorter and more inferiorly placed between the legs.

Short stature, brachydactyly, small ears, and a pattern of minor anomalies in brother and sister born to consanguineous parents: A Hitherto Unreported syndrome?

A 13-year-old boy and his 28-year-old sister had short stature, obesity, and a pattern of minor anomalies including a sloping, narrow forehead; small ears; a narrow nose with prominent bridge and long septum; short upper lip; receding mandible; and short limbs with brachydactyly and clinodactyly of little fingers. The boy also had hypoplastic external genitalia and elevated FSH. Both are of normal intelligence. There is remote consanguinity of the (normal) parents. The 2 sibs probably represent a hitherto un-recognized syndrome of possibly autosomal recessive inheritance.

Orofaciodigital syndrome type IV (Mohr-Majewski syndrome) with severe expression expanding the known spectrum of anomalies.

We present a male infant with hypertelorism, median pseudo-cleft of the upper lip and cleft palate, lobulated tongue, hypoplastic larynx and epiglottis, mesomelic shortening of limbs with particularly short and broad tibiae, polydactyly of the upper limbs, severely hypoplastic external genitalia with anorchidism, anal atresia, severe congenital heart defect, and renal agenesis. These features show considerable overlap with severe Majewski type short rib-polydactyly syndrome and so expand the known spectrum of anomalies in orofaciodigital syndrome type IV.

Fryns syndrome: report on 8 new cases.

The name Fryns syndrome was given to a new variable multiple congenital anomaly syndrome, almost always lethal, described in 1978, and now known to be autosomal recessive. Since that date, 20 patients have been reported in the literature. We describe 8 new cases, 6 of which were diagnosed in a series of 112,276 consecutive births (livebirths and perinatal deaths). The prevalence of this syndrome can be estimated to be around 0.7 per 10,000 births. These new cases confirm that the most frequent anomalies are diaphragmatic defects, lung hypoplasia, cleft lip and palate (often bilateral), cardiac defects (septal defects and aortic arch anomalies), renal cysts (type II, III or IV), urinary tract malformations, and distal limb hypoplasia. Most patients also have hypoplastic external genitalia and anomalies of internal genitalia (bifid or hypoplastic uterus, immature testes). The digestive tract is also often abnormal: duodenal atresia, pyloric hyperplasia, malrotation and common mesentery are present in half of the patients. When the brain was examined, more than half were abnormal (Dandy-Walker anomaly and agenesis of corpus callosum). A few patients demonstrated cloudy cornea. We examined the eyes of three patients histologically: two of them showed retinal dysplasia with rosettes and gliosis of the retina, thickness of posterior capsula of lens and irregularities of the Bowman membrane. Four of our cases were diagnosed prenatally between 24 and 27 weeks. It is to be expected that prenatal diagnosis will be made often and earlier in the future, as the spectrum of anomalies of the Fryns syndrome can easily be evidenced by sonography.

Derivative chromosomal structures from a ring chromsome 4.

This report describes the results from cultured lymphocytes studied at metaphase, anaphase, and interphase from an individual with a ring chromosome 4. A ring was present in 90.1% of metaphases. Special attention was directed towards the occurrence of derivative chromosomal structures, such as partially duplicated and triplicated rings, tricentric rings, chains of 3 interlocked rings, rod-shaped chromosomes, "pulverized" rings, and others. The clinical features of the individual (small stature and impaired mental development, hypoplastic thumbs, ptosis palpebrae hypoplastic external male genitalia, abnormal dermatoglphic pattern) did not conform to a specific phenotype.

APPARENT CUTIS LAXA, MICROCEPHALY, CHD, POLYCYSTIC KIDNEYS, HYPOGENITALISM - A “NEW” SYNDROME

A complete dissection was done on a 7 day, 46 XY infant with mild IUGR and a syndrome of microcephaly, fleeting forehead, high bridge of nose, mongoloid slanting of palpebral fissures, micrognathia, congenital heart disease, hypoplastic external genitalia with penile hypospadias, foot deformities and remarkable redundancy of skin, especially over “nape of neck” and extremities.Anatomical and histological studies showed an apparent absence of elastic fibers in skin, heart defects (absence of superior vena cava, left superior vena cava entering an enlarged coronary sinus, large ASD, triple coronary arteries, PDA, bicuspid pulmonic valve), hypoplastic inguinal testes, and bilateral Potter Type II dysplastic, polycystic kidneys. These findings are interpreted as a (genetic?) multiple congenital anomaly syndrome with apparent mosaic pleiotropy rather than as a connective tissue dysplasia with relational pleiotropy. Skin findings may reflect fetal lymphedema; in a similar patient (Kaye, et. al., 1974 Am. J. Pis. Child. 127:115) pitting edema of feet was seen. This condition may represent a new syndrome.