Hypothalamic-pituitary-gonadal function in two infants with Smith-Lemli-Opitz syndrome.

We report on the hypothalamic-pituitary-gonadal function in 2 male infants with the Smith-Lemli-Opitz (SLO or RSH) syndrome. Both infants had abnormal external genitalia. Basal and LHRH stimulated plasma gonadotropins were normal for age (1 month). Plasma testosterone, androstenedione, and dehydroepiandrosterone sulfate were normal for age and sex. Some forms of congenital adrenal hyperplasia (17,20-desmolase deficiency, 17 alpha-hydroxylase deficiency, and 3 beta-hydroxysteroid dehydrogenase deficiency) were ruled out by hormonal studies. The endocrinological findings indicate a normal hypothalamic-pituitary-gonadal function and a normal adrenal steroid biosynthesis in these 2 patients. A partial androgen receptor defect causing the genital malformations seems possible in one patient. Whether 5 alpha-reductase deficiency is the cause of the male pseudohermaphroditism in SLO syndrome remains the subject of future studies.     

Smith-Lemli-Opitz syndrome in two 46,XY infants with female external genitalia

Two infants with features of the Smith-Lemli-Opitz (SLO) syndrome were found to have a 46,XY karyotype and female external genitalia. Autopsies showed normal testes for age with normal Wolffian duct structures and without Müllerian duct derivatives. This failure of masculinization of the external genitalia is an unusual finding and may represent the extreme of a spectrum of the genital anomalies commonly seen in males with this autosomal recessive syndrome. An endocrine evaluation on one of these infants at 3 months suggested unusually low testosterone production and meagre response to stimulation with human chorionic gonadotropin (hCG). The failure of complete masculinization of external genitalia in some cases of SLO syndrome may be due to inadequate testosterone production in utero.     

Clinical and biochemical spectrum of patients with RSH/Smith-Lemli-Opitz syndrome and abnormal cholesterol metabolism

RSH/Smith-Lemli-Opitz (RSH/SLO) syndrome is an autosomal recessive malformation syndrome recently shown to be associated with a severe deficiency of cholesterol biosynthesis and markedly elevated plasma and tissue levels of 7-dehydrocholesterol (7-DHC), the immediate precursor of cholesterol in the Kandutsch-Russell biosynthetic pathway. Because these biochemical abnormalities permit a reassessment of RSH/SLO on biochemical criteria rather than less specific physical criteria, we review here the clinical and biochemical characteristics of our first 80 patients with abnormally increased levels of 7-DHC. The study population included 68 index patients and 12 additional relatives identified by quantification of 7-DHC and cholesterol in plasma, amniotic fluid, or cultured fibroblasts, lymphoblasts, or amniocytes. As demonstrated in other clinical syndromes when redefined biochemically, we have found a wider range of clinical expression of RSH/SLO than previously recognized. These newly recognized atypical RSH/SLO patients included several with no malformations other than syndactyly of the toes and, at the other extreme, patients with frank holoprosencephaly or multiple visceral anomalies who died in utero. Syndactyly of toes 2 and 3 was the most common malformation, occurring in all but one of 80 patients. The best biochemical predictor of clinical severity was the plasma cholesterol level, which decreased with increasing clinical severity. However, at least 10% of patients, including one newborn infant, had normal cholesterol levels at the time of diagnosis and would have been missed without specific quantification of 7-DHC. Not unexpectedly, several patients carrying a clinical diagnosis of RSH/SLO were found to have normal levels of all plasma sterols and apparently normal cholesterol biosynthesis in cultured cells. A comparison of the frequency of anomalies in our biochemically identified patients with similar data from previously reported clinical series suggests that up to 25% of reports of RSH/SLO in the literature may describe genetic conditions other than RSH/SLO with 7-DHC-emia. Am. J. Med. Genet. 68: 263–269, 1997. © 1997 Wiley-Liss, Inc.     

Abnormal cholesterol metabolism in the Smith-Lemli-Opitz syndrome: Report of clinical and biochemical findings in four patients and treatment in one patient

We report on four patients with the Smith-Lemli-Opitz (SLO) syndrome who appear to have a defect in cholesterol biosynthesis. The initial results of therapy of one of the patients with cholesterol and bile acids to correct her metabolic abnormalities are described. This finding provides a biochemical marker to help in the diagnosis of this syndrome, may provide insight into the pathogenesis of this disorder, and have therapeutic and prenatal diagnostic implications as well. © 1994 Wiley-Liss, Inc.     

Guadalajara camptodactyly syndrome

Two sisters, aged 18 and 11 years, were found to have an intrauterine growth retardaion-malformation syndrome which included camptodactyly as a typical sign. The overall analysis of the clinical and radiological findings permitted the individualization of a distinct entity. The family data suggested autosomal recessive inheritance.     

Aarskog syndrome in a brazilian boy born to consanguineous parents

We report on a Brazilian boy (F = 1/16) born to consanguineous parents and presenting with typical Aarskog syndrome. Genetic aspects and phenotypic manifestations of this patient are compared with those of the (X-linked) Aarskog syndrome and with the autosomal recessive faciodigitogenital syndrome. © 1992 Wiley-Liss, Inc.     

Oculocerebral syndrome with hypopigmentation (Cross syndrome): report of a new case

A syndrome of ocular and cutaneous hypopigmentation, severe mental retardation with spastic tetraplegia and athetosis was first observed by Cross in three siblings of an inbred Amish family. Since then, seven other patients, three sporadic and four with familial recurrence, have been reported in the literature, confirming the autosomal recessive inheritance. The clinical spectrum of the syndrome has been expanded to include true developmental defects of the CNS such as cystic malformation of the posterior fossa of the Dandy-Walker type. We report a new case of Cross syndrome.     

Cholesterol and bile acid replacement therapy in children and adults with Smith-Lemli-Opitz (SLO/RSH) syndrome

Tint et al. [N Engl J Med 1994, 330:107–113], working with blood samples from the Smith-Lemli-Opitz syndrome (SLOS) patients of Irons and Elias showed the biochemical basis of this disorder to be a cholesterol biosynthesis defect [Irons et al., Lancet, 1993, 341:1414]. Based on this finding, clinical protocols for cholesterol and bile acid replacement therapy were established in a few centers including the University of Pittsburgh. We report our experience with bile acid and/or cholesterol replacement therapy in six patients with SLOS, now aged 3–27 years, with a confirmed biochemical diagnosis. Levels of plasma cholesterol and 7-dehydrocholesterol were correlated with periodic clinical evaluations over 8–27 months of therapy. There was a marked improvement in the growth of all the children. There was also an increase in the plasma cholesterol level in all the children and an overall increase in their percent sterol as cholesterol. Subjective improvement was also noted in their development. Although there was no significant change in the plasma cholesterol level of the older patients, there was a marked improvement in their behavior and in their quality of life. Am. J. Med. Genet. 68:315–321, 1997. © 1997 Wiley-Liss, Inc.     

Dandy-Walker malformation in Ellis-van Creveld syndrome

We report on 2 Old Order Amish patients with Ellis-van Creveld (EvC) syndrome and the Dandy-Walker malformation; a similar case is noted in the literature. Pedigree analysis of our patients documents extensive inbreeding in successive generations. Considering the rarity of EvC syndrome and Dandy-Walker malformation as isolated malformations, the appearance of both in our 2 patients plus the patient in the literature suggests that Dandy-Walker malformation may be a manifestation in the EvC syndrome. However, in this isolate the coincidental occurrence of 2 rare recessive traits cannot be excluded.     

Dandy–Walker malformation in the Meckel syndrome

The Meckel syndrome is an autosomal recessive condition and includes a heterogeneous group of CNS malformations, most frequently occipital encephalocele. We report on 2 sibs and one other unrelated case with Meckel syndrome in whom the CNS anomaly was the Dandy–Walker malformation, an association not previously described. The criteria used to diagnose the Meckel syndrome are also reviewed.     

Normal intelligence in two children with carpenter syndrome

Previous reports have noted a constant association between the Carpenter syndrome (acrocephalopolysyndactyly, type II) and mental retardation. We report two patients with this condition with normal intelligence. These observations indicate that mental deficiency is not necessarily a component of the Carpenter syndrome and that early surgical correction of the craniosynostoses may improve the chances of normal mentality.     

Familial neonatally lethal syndrome of hypoplastic left heart,absent pulmonary lobation,polydactyly, and talipes,probably Smith-Lemli-Opitz (RSH) syndrome

Two siblings, one a male pseudohermaphrodite and the other female, died on the first day of life. In both instances pregnancy was complicated by polyhydramnios. At autopsy each was found to have multiple abnormalities, some concordant, others discordant. The concordant ones were hypoplastic left-heart complex, absent pulmonary lobation, polydactyly, bilateral talipes, and, on microscopic examination, some large atypical cells in the pancreatic islets. Chromosome cultures failed to grow. As far as is known parents were unrelated. Autosomal recessive inheritance is considered a possible cause, and the infants are thought to have the most severe form of the so-called Smith-Lemli-Opitz (RSH) Syndrome.     

Cardiovascular malformations in Smith-Lemli-Opitz syndrome

We reviewed 215 patients (59 new, 156 from the literature) with Smith-Lemli-Opitz syndrome (SLOS), and found that 95 (44%) had a cardiovascular malformation (CVM). Classifying CVMs by disordered embryonic mechanisms, there were 5 (5.3%) class I (ectomesenchymal tissue migration abnormalities), 56 (58.9%) class II (abnormal intracardiac blood flow), 25 (26.3%) class IV (abnormal extracellular matrix), and 5 (5.3%) class V (abnormal targeted growth). Comparing the frequencies of individual CVMs in this series with a control group (the Baltimore-Washington Infant Study), there were 6 individual CVMs which showed a significant difference from expected values. When frequencies of CVMs in SLOS were analyzed by mechanistic class, classes IV and V were significantly more frequent, and class I significantly less frequent, than the control group. Although CVMs in SLOS display mechanistic heterogeneity, with an overall predominance of class II CVMs, the developmental error appears to favor alteration of the cardiovascular developmental mechanisms underlying atrioventricular canal and anomalous pulmonary venous return. This information should assist the clinical geneticist evaluating a patient with possible SLOS, and should suggest research direction for the mechanisms responsible for the SLOS phenotype. Am. J. Med. Genet. 68:270–278, 1997. © 1997 Wiley-Liss, Inc.     

The Floating-Harbor syndrome: two affected siblings in a family

In this report we describe two siblings with pre-and postnatal growth retardation and clinical signs and symptoms most compatible with the diagnosis of Floating-Harbor syndrome. The oldest sibling, a girl, died in the first year of life from recurrent infections. The younger sibling, a male, is now 16.5 years old and mildly mentally retarded.     

Borderline normal intelligence in the Smith-Lemli-Opitz (RSH) syndrome

We report two sibs with the Smith-Lemli-Optiz (RSH) syndrome and intelligence in the borderline normal range. The proposita has all the features of the syndrome; however, her brother shows fewer signs, indicating that considerable variability of expression may exist for this autosomal recessive trait. Nearly all previous cases had severe to profound mental retardation. The incidence of the syndrome in British Columbia is approximately 1/40,000 live births, giving a heterozygote frequency of about 1/100.     

A new short rib syndrome: Report of two cases

We describe two unrelated malformed infants who died shortly after birth and who had multiple congenital anomalies including hydrops and ascites, facial abnormalities (with median cleft of the upper lip), narrow thorax, protuberant abdomen, and short, bowed limbs. Postmortem radiographs showed very short ribs and disproportionately short long tubular bones; no metaphyseal abnormalities were present. Comparison with earlier described short-rib/short-rib-polydactyly syndromes suggest that the disorder present in our two cases is a new type of short-rib syndrome. One of our patients was born to a consanguineous couple; in a subsequent pregnancy, real-time ultrasonography in the second trimester showed that the female fetus had the same abnormalities as its sib. Diagnosis was confirmed after elective abortion. This suggests that this short-rib syndrome may be an autosomal recessive disorder.     

An apparently new autosomal recessive syndrome with facial dysmorphism, macrocephaly, myopia and Dandy-Walker malformation

In this report we describe an apparently new MCA-MR syndrome with Dandy-Walker malformation in three severely mentally retarded siblings born to normal, non-consanguineous parents. In addition, they presented macrocephaly, facial dysmorphism, extreme myopia and brachytelephalangy with short and broad finger-nails.     

Parental consanguinity in two sibs with omodysplasia

Two sibs with omodysplasia were born to phenotypically normal but consanguineous parents. They had severe micromelic dwarfism, facial anomalies, and mental retardation. One had a congenital heart defect. The radiographic findings are typical: hypoplastic distal end of the humerus with radioulnar diastasis. Parental consanguinity and clinical manifestations in 2 sibs suggest autosomal recessive inheritance. © 1994 Wiley-Liss, Inc.     

Dextrocardia with and without situs viscerum inversus in two sibs

We describe two sibs born to consanguineous Sicilian parents who died of severe congenital heart malformation. Both had dextrocardia; however, only the girl had situs viscerum inversus. At necropsy she was found to have a right spleen and right pulmonary isomerism (three lobes in each lung, as commonly found in the asplenia syndrome). This observation, together with other literature reports, suggest that isolated dextrocardia, situs viscerum inversus, and the asplenia-poly-splenia complex may be different end results of a unique dysmorphogenetic process involving the embryonic midline.