Familial Prader-Willi syndrome.

Three adult sisters with previously unrecognized Prader-Willi syndrome (PWS) demonstrated the six diagnostic features of this congenital condition: neonatal hypotonia, hypomentia, hypogonadism, obesity, short stature, and dysmorphism. Detailed endocrine investigations were performed, including ovarian biopsy in the propositus. HLA genotype A2 was present in each patient. The normal high-resolution prometaphase karyotypes indicated heterogeneity; the absence of the deletion 15q12 frequently found in patients with sporadic PWS distinguished this sibship as representing a possible autosomal recessive type of PWS. Current evidence suggests that the diagnosis of PWS may be often overlooked. Increased clinical awareness of the features of PWS should result in prompt diagnosis and optimal management of affected patients, together with increased understanding of this enigmatic condition.

Acanthosis nigricans in a patient with streak gonads.

Acanthosis nigricans (ACN) is associated with ovarian disorders or abnormalities of carbohydrate metabolism. We saw a 21-year-old woman who had primary amenorrhea and ACN. Results of endocrine studies showed anovulation and low serum estradiol levels with increased gonadotropin concentrations. Laparoscopic examination disclosed bilateral streak gonads; the ovaries were completely replaced by fibrous tissue. Cultures of peripheral lymphocytes, skin fibroblasts, and the right and left ovaries demonstrated normal female karyotype 46XX in all mitoses studied. An autoimmune disorder was excluded by the absence of antithyroid and antiadrenal antibodies. Specific antibodies against ovarian proteins were also absent. A glucose tolerance test demonstrated fasting hyperinsulinemia and exaggerated serum insulin response to the glucose load. The observations in this patient exclude a primary pathogenic role for the ovary in the production of ACN; they also lend further support to a connection between the cutaneous disorder and insulin resistance.

RET mutation screening in familial cutaneous lichen amyloidosis and in skin amyloidosis associated with multiple endocrine neoplasia.

In several families, multiple endocrine neoplasia type 2A (MEN 2A) has been found in association with cutaneous lichen amyloidosis. It has been debated, however, whether the skin amyloidosis found in MEN 2A families, localized exclusively in the interscapular area, represents the same anomaly as that found in autosomal dominant familial cutaneous lichen amyloidosis, which is more generalized. We screened two MEN 2A families with associated skin amyloidosis for germline mutations in the RET gene responsible for the MEN 2A cancer syndrome, and found the same mutation characteristic of MEN 2A in both families. We also screened probands from three pedigrees with familial cutaneous lichen amyloidosis for RET mutations. In none of the RET coding and flanking intronic sequences was a mutation detected. This most probably indicates that skin amyloidosis found in some MEN 2A families and familial cutaneous lichen amyloidosis are different conditions. Consequently, patients with apparent familial cutaneous lichen amyloidosis do not appear to be at risk for MEN 2A.

Sacral meningocele with conotruncal heart defects: a possible autosomal recessive trait.

Three of four siblings had sacral meningocele with subsequent development of hydrocephaly; two died during the neonatal period due to conotruncal heart defects (transposition of the great vessels and truncus arteriosus type I, respectively). An in utero diagnosis of open neural tube defect was made on the third sibling; persistent slightly elevated alpha-fetoprotein levels in amniotic fluid and increased number of rapidly adhering cells in short term amniotic cell culture were found. The unique combination of sacral meningocele and conotruncal malformations in this sibship suggests a new autosomal recessive condition. It also emphasizes the heterogeneity of both the open neural tube defects and congenital heart defects. Awareness of this variant is necessary in regard to the 25% recurrence risk instead of the 3% to 5% recurrence risk given for both congenital heart defects and open neural tube defects as isolated anomalies. The difficult prenatal diagnosis for the small neural tube defect should be appreciated.

Autosomal recessive type of whistling face syndrome in twins.

A report of concordant monochorionic, diamnionic like-sex twins with whistling face syndrome is presented. The diagnosis was based on the characteristic facies with prominent supraorbital ridge, sunken eyes, telacanthus, short nose and colobomata of the nostrils, long philtrum, high narrow palate, and marked microstomia with puckered lips and an "H"-shaped cutaneous dimpling on the chin. The hands showed symmetrically clenched fingers with camptodactyly and ulnar deviation. The feet demonstrated mild bilateral talipes equinovarus. HLA studies to determine the zygosity of the twins showed discordance in HLA haplotypes, which indicated dizygosity. The pedigree analysis showed normal nonconsanguineos parents, and no other family members had the syndrome. The findings support the existence of an autosomal recessive type of whistling face syndrome.

Fucosidosis type 2.

Two siblings, 9 and 4 1/2 years old, had alpha-L-fucosidase deficiency, angiokeratoma, progressive psychomotor retardation, neurologic signs, coarse facila features, and dysostosis multiplex. It appears that genetic heterogeneity is present in fucosidosis; there are at least two types. In type 1, patients have no vascular lesions, but have rapid psychomotor regression, severe and rapidly progressing neurologic signs, elevated sodium and chloride excretion in the sweat, and fatal outcome before the sixth year. In type 2, patients have angiokeratoma, milder psychomotor retardation and neurologic signs, longer survival, and normal salinity in the sweat. Quantitative studies on erythrocytes and in saliva disclosed severely increased expressions of Lea and Leb. Biopsies of skin and gingiva showed alterations as seen in angiokeratoma. There was also evidence of lysosomal storage in vascular endothelium, eccrine sweat gland epithelium, and fibroblasts of the skin.

Hypothesis: Jadassohn nevus phakomatosis: a paracrinopathy with variable phenotype.

It has been postulated that the phakomatoses are paracrine growth regulation disorders (paracrinopathies). To determine how Jadassohn nevus phakomatosis (JNP) may fit such a pathogenetic model, a phenotype analysis of 13 propositi with JNP and a review of most reported JNP patients were done. The phenotypes of the propositi and the reviewed patients showed a great variability from a solitary congenital epidermal nevus to extensive cutaneous lesions with associated severe non-cutaneous anomalies. Review of long-term observations of JNP patients demonstrated considerable phenotypic changes within and beyond the boundaries of the nevi. The changes included a multitude of postnatal rare benign and/or malignant tumors and unusual manifestations: renal rickets, hepatomegaly, visceral cysts, vasculopathy, and even gangrene. Thus, a life-long predisposition to dysregulation of paracrine growth factors (GFs, regulatory peptides, peptide regulatory factors, and cytokines), foremost somatomedin-C (Sm-C, IGF-I), epidermal, fibroblast, platelet-derived GFs, and transforming GF-beta is implied. Laboratory evidence for the presumed GF dysregulation in the phakomatoses came from tissue culture study of patients with neurofibromatosis type 1 (NF-1). Compared to controls their "normal" skin showed ultrastructural changes of markedly increased number of melanin macroglobuli within the melanocytes. Paracrine GFs as relevant to hamartomatous growth were incriminated by radioimmunoassays of cutaneous neurofibromas showing two-fold or greater increase of Sm-C levels compared to the levels in the adjacent skin. Thus, NF-1 appears to be a paracrinopathy. JNP shows many more dynamic changes throughout the life span of the patients than NF-1. In the near future paracrinology may aid endocrinology and oncology in treating patients with disorders of these three growth mechanisms in man.

Gestational diabetes mellitus (class A): a human teratogen?

Between January 1, 1982 and December 31, 1992 we evaluated 200 children of mothers with pregestational or gestational diabetes mellitus through the University of South Florida Genetics/Dysmorphology Clinics. They were a portion of the 22,100 families seen during that period. Pregnant women with diabetes mellitus were not part of this study. One hundred and fifty-two of the 200 were offspring of mothers with gestational diabetes (classes A1 and A2). Class B1 was not encountered as a subclass of gestational diabetes in this series. Twenty-four of the 152 did not have anomalies. Forty-one of the 152 had another primary diagnosis to account for their malformations. Eighty-seven of the 152 had a constellation of anomalies or solitary structural defects as seen in diabetic embryopathy. Chromosomal, monogenic, and other teratogenic causes were excluded. The observed phenotypes matched those seen in offspring of mothers with diabetes mellitus classes B2 to T. They also corroborated the animal studies, indicating that the embryopathy of gestational diabetes has a pathogenesis similar to that in classes B2 to T, and recent epidemiological studies showing a statistically significant increase of anomalies as in diabetic embryopathy in the offspring of gestational diabetes mothers. As per established obstetric practice the testing for gestational diabetes was after gestation 16 weeks. Thus, it was impossible to prove that the anomalies of the 87 propositi were due to gestational diabetes. However, the anomalies occurred during organogenesis as in the other diabetic classes, and inferred that gestational diabetes is a human teratogen. If so, common "idiopathic" malformations may be actually caused by undiagnosed maternal gestational diabetes.

The cytogenetic controversy in the Prader-Labhart-Willi syndrome.

A patient with Prader-Labhart-Willi syndrome (PLWS) was found to have mosaic partial trisomy 15: 46,XY/47,XY, + del(15) (pter leads to q1.3:) in both lymphocytes and fibroblasts. Thus, another novel aberration is added to the spectrum of chromosome abnormalities seen in this syndrome. The spectrum includes deletion of the short arm of chromosome 15, interstitial deletion of 15q1.2, inverted duplication of 15p (tetrasomy 15p), partial trisomy 15 different from that encountered in this patient, and a variety of aberrations involving other chromosomes. A hypothesis that the chromosome aberrations are due to a presumed gene for the PLWS may have merit and could be tested in the laboratory by exposing chromosomes of patients with PLWS to mutagens to search for secondary chromosome derangements.

Cohen syndrome: further delineation and inheritance.

Four sibs, 2 males and 2 females, were found to have the Cohen syndrome. All had moderate mental retardation, microcephaly, hypotonia, and narrow hands and feet with elongated fingers and toes; 3 were short of stature (2.0-3.5 SD below the mean) with weight between 10th and 50th centile and truncal obesity. Most of the facial characteristics of the syndrome were present: exotropia, prominent ears, short philtrum, and high nasal bridge. Each manifestation varied in severity from one sib to the other. The younger girl also had rheumatoid arthritis. Mild delay of puberty was described in 3 of the sibs. However, one of them has delivered a male infant with normal appearance whose psychomotor development has been normal (as of 9 months). No endocrine problems were documented in the sibship. All patients had normal chromosomes. The data on this sibship support the hypothesis of autosomal recessive inheritance of the Cohen syndrome. Microcephaly and short stature should be stressed as frequent manifestations of the syndrome. The variable expressivity, even among sibs, may be responsible for the paucity of reports on the mildest forms of the Cohen syndrome.

Phenotypic overlap of Ehlers-Danlos syndrome types IV and VIII.

An 18-year-old Caucasian woman has been followed since age 12 years for Ehlers-Danlos syndrome (EDS) with easy bruisability and "cigarette paper scars." Her chief complaint at age 17 years was tooth mobility, especially in the anterior mandible, necessitating the removal of the four incisors. Initial biochemical analysis of cultured skin fibroblasts indicated the presence of pepsin-sensitive type III collagen. Subsequent analysis of cultured skin fibroblasts by the same laboratory and another laboratory found no abnormality in the type III collagen with or without protease treatment. This is in distinction to the finding of abnormal type III collagen in the only two reported patients with EDS and early-onset periodontitis who have had collagen analyses. One of them was diagnosed as EDS type IV and the other as EDS type VIII, although the defects of type III collagen were consistent with EDS type IV. The defect in type III collagen in some patients with early periodontitis and the considerable overlap of the clinical manifestations of EDS types IV and VIII point out the need for further studies of collagen formation and maturation in any patient who has early periodontitis and who has been classified with EDS type IV or VIII.

Penile neurofibromas.

Unless omitted and underreported, penile neurofibromas are rare. Between January 2, 1982 and December 31, 1997 through the USF Regional Genetics Program we evaluated 566 propositi with suspected or clinically diagnosed neurofibromatosis (NF1, NF2, segmental NF=NF5, NF/Noonan syndrome, familial café-au-lait macules, and solitary neurofibroma, NF). These index cases were part of 32,715 families evaluated during the period. NF1 was the diagnosis in 361; 2 of them had penile NFs. A toddler presented with congenital plexiform NF of the penile shaft and another propositus developed two small subcutaneous NFs, on the penile shaft and on the left scrotal wall, respectively. A review documented 26 additional patients with penile NF. As to the pathogenesis of the NF1 lesions, a paracrine growth model including the multiple levels of regulation of expression of the NF1 gene appeared more plausible than the loss of heterozygosity (LOH) model, which ignores the complexity of the paracrine growth mechanism.

Ankyloblepharon filiforme adnatum.

We treated 4 infants with ankyloblepharon filiforme adnatum (AFA), an uncommon anomaly in which the apposing eyelid margins are connected by abnormal tissue strands. One infant had AFA alone, one had Hay-Wells syndrome, characterized by ectodermal dysplasia, and the other 2 had chromosome abnormalities, trisomy 18, and complex chromosome rearrangement, with visceral malformations. Despite heterogeneity and phenotypic variability, these developmental abnormalities shared (1) involvement of tissues growing in apposition and (2) temporal overlap of their occurrence. This suggests a common defect in the mechanism(s) that regulate tissue fusion at multiple sites during development.

"Vascular neurofibromatosis" and infantile gangrene.

An 11-year-old boy with slowly progressive gangrene caused by vasculopathy similar to that of neurofibromatosis (NF) type 1 (NF I; von Recklinghausen disease [NFvR]) and a newborn girl with idiopathic gangrene with vascular changes resembling those of NFvR prompted the analysis of all 105 propositi with NF (NF I and NF II) evaluated between January 2, 1982, and December 31, 1986, at the genetics clinic of University of South Florida. They were analyzed for renal hypertension, symptomatic ischemia, and known vascular changes. One additional 27-month-old boy with NFvR was found to have extensive vascular changes with renal hypertension. The vasculopathy indicated asymmetric over/undergrowth of cellular and extracellular components of the vascular wall and implied dysregulation of the paracrine growth mechanism. Immunocytochemical studies of affected vessels were done only in the 11-year-old boy and showed positive neuron-specific enolase, S-100 protein, and glial fibrillary acidic protein (GFAP) reactions indicative of Schwann cell involvement. The vascular changes in children with NFvR are mostly asymptomatic; however hypertension secondary to renal artery stenosis and/or Moya-moya disease have been reported infrequently. Our patients with vasculopathies provoked thoughts in regard to the so-called vascular NF, its place in current NF nomenclature and classification, relationship to fibromuscular dysplasia (FMD), and possible role in infantile gangrene.

Expanded phenotype of cranioectodermal dysplasia (Sensenbrenner syndrome)

Cranioectodermal dysplasia (CED) is an autosomal recessive condition characterized by defects of ectoderm-derived structures and characteristic bone anomalies. We report on a 27-month-old Caucasian girl with CED, pre- and postnatal growth retardation, microcephaly, hypoplasia of the posterior corpus callosum, photophobia, and aberrant calcium homeostasis. Since new traits were encountered, we reviewed all reported patients and one unpublished case and compared the frequency rates of the individual manifestations. The findings present in all patients are dolichocephaly and rhizomelia. Ectodermal dysplasia manifestations are variable. Short thorax and heart defect are inconsistent. Previously unreported anomalies include growth deficiency, delayed psychomotor development, microcephaly, photophobia, and abnormal calcium homeostasis. These clinical manifestations may facilitate the diagnosis of this condition.

Clitoromegaly in neurofibromatosis.

Genitourinary neurofibromas are rare and clitoral involvement in neurofibromatosis (NF) has been reported infrequently. However, when it occurs, clitoromegaly is often the presenting sign. In many cases, it is congenital. In 236 families with type 1 neurofibromatosis (NF-1) evaluated through the USF Regional Genetics Program between January 1982 and September 1993, four patients had clitoral involvement. In three, involvement was limited to the clitoris. Biopsy/surgical excision in two of them showed a neurofibroma in one and non-specific hamartomatous soft tissue overgrowth in the other. In the fourth patient, the involvement was asymmetric and extended to the labia majora and mons pubis. Endocrine studies and chromosomes in all patients were normal; there was no exposure to androgens, progestins, or coumadin. There was no gestational history of maternal luteomas. Review of the literature documented 26 patients with NF and clitoral involvement. Clitoral involvement in NF-1 appears to be more common than previously reported and the differential diagnosis of ambiguous genitalia should include clitoromegaly due to NF. Pathogenesis of clitoral lesions appears similar to other lesions of NF. Biopsy of such lesions appears to be justified only when malignancy is suspected.

Unique mosaicism in Prader-Labhart-Willi syndrome--a contiguous gene or aneuploidy syndrome?

A 16-year-old boy with Prader-Labhart-Willi syndrome (PLWS) had hypotonia, feeding difficulties, failure to thrive, strabismus and bilateral inguinal hernias with cryptorchidism during infancy followed by hyperphagia, marked early-onset obesity with insulin-dependent diabetes mellitus and necrobiosis lipoidica diabeticorum, short stature, hypogonadotropic hypogonadism and some of the facial characteristics of the individuals with the PLWS. IQ is estimated around 90. Cytogenetic studies showed mosaicism: 45,X, t(Y;15) with partial deletion 15 (15pter----15q12); 46,X, t(Y;15), dic (15)(15pter----15q12::15q12----15pter) and 47, X, t(Y;15), dic(15), dic(15). The dic(15) was bisatellited, NOR-positive on both arms and represented inv dup(15). Thus, the 2 lines with the dic(15) showed partial trisomy 15 (15pter----15q12) and partial pentasomy 15 (15pter----15q12), respectively. The cell line ratios were different in lymphocyte and fibroblast cultures. The unique cytogenetic findings in this patient, the reports of a variety of chromosome 15 aberrations in PLWS, as well as aberrations of other chromosomes, suggest that the condition is a contiguous gene syndrome rather than an aneuploidy syndrome.

Facioscapulohumeral dystrophy with cochlear hearing loss and tortuosity of retinal vessels.

We report on a mother and her three children with facioscapulohumeral dystrophy (FSHD), sensorineural hearing loss, and marked tortuosity of the retinal vessels. Initially the children presented with speech difficulties and hearing deficit. Hearing loss ranged from mild to severe. An audiologic evaluation, including brain stem auditory evoked responses in all patients, indicated a cochlear origin of hearing loss and intact pathways from the cochlea to the temporal lobe. The association of FSHD with hearing loss and tortuosity of the retinal vessels suggests previously unrecognized pleiotropy of FSHD (McKusick 15890) or a "new" type of FSHD.

Physical growth in Brachmann-de Lange syndrome.

Growth in 30 patients with Brachmann-de Lange syndrome (BDLS) was evaluated and found to be deficient in 27/30, with 17/27 having intrauterine growth retardation (IUGR). In 12/27 patients, endocrine evaluations have been completed. Seven of 12 were normal and 4/12, one with empty sella, had "classical" growth hormone deficiency with extreme short stature, markedly delayed skeletal maturation and subnormal growth hormone secretion in response to provocative stimuli. One of 12 patients had discordance between insulin growth factor I levels and growth hormone responses to insulin and clonidine suggestive of end organ resistance to growth hormone. It appears that the hypothalamic-pituitary function is compromised in at least some BDLS patients. Thus, endocrine evaluations are warranted for the patients with short stature.

Bronchopulmonary-foregut malformations: a continuum of paracrine hamartomas?

The bronchopulmonary-foregut malformations (BPFM) are usually sporadic, solitary cystic hamartomas involving conducting airways, arteries, venous drainage, and lung parenchyma. Transitional, compound hamartomas exist, and only their morphology is well-known. Between 1984-1994 we encountered and studied 10 unrelated patients and a stillborn infant with BPFM (out of 24,000 families). Ten were diagnosed in utero and one at birth as having congenital cystic adenomatoid malformation of the lung (CCAML). Postnatally, two diagnoses (20%) were corrected to bronchogenic cyst (BC) and diaphragmatic hernia, respectively. Bilateral lung involvement was present in 1 patient, and in 2 there was a considerable macroscopic regression of the hamartoma. Histologic studies of the six resected CCAML confirmed the diagnosis and implied dysregulated paracrine growth with its cellular and extracellular growth factors, protooncogenes, oncogenes, cytokines, cell-adhesive molecules, and receptors of these regulatory peptides, and their complex interactions as developmental morphogens in time and space.