Complex consanguinity associated with short rib-polydactyly syndrome III and congenital infection-like syndrome: a diagnostic problem in dysmorphic syndromes

Short rib-polydactyly syndromes (SRPS) are a heterogeneous group of recessively inherited lethal skeletal dysplasias. Four types have been recognised. However, overlap in the clinical and radiological features of the four types has led to difficulties in distinguishing between them. The congenital infection-like syndrome is an autosomal recessive syndrome characterised by mental retardation, microcephaly, seizures, and intracranial calcifications. We report a complex consanguineous family of Baluchi origin in whom short rib-polydactyly type III and congenital infection-like syndrome are segregating. Four children inherited SRPS III, one inherited congenital infection-like syndrome, and one inherited both. Although the radiological features in all the children with SRPS in this report were typical of type III, there was overlap in the clinical features with the other types of SRP syndromes. Furthermore, the child who inherited both SRPS III and congenital infection-like syndrome had CNS malformations in addition to periventricular calcification. CNS malformations have been described in SRPS types II and IV but not type III. This report further highlights the overlap between the different types of SRP syndrome. Moreover, it draws attention to the importance of considering the possibility of two recessive syndromes in the same child in complex consanguineous families when features overlap two syndromes.     

Esophageal dysmotility in brothers with an FG-like syndrome

We present 4 brothers with developmental delay, minor anomalies, and symptoms due to gastrointestinal dysmotility. There was some resemblance with FG syndrome, although none of the brothers had sufficient findings to make this diagnosis. The index case presented with at age 1 month with screaming episodes, mild gastro-esophageal reflux (GER), and severe constipation. Esophageal manometry studies were consistent with the diagnosis of "nutcracker esophagus." Symptomatic and manometric improvement followed treatment with oral calcium channel blockers. Two older and less severely affected brothers had similar manometric findings but did not require treatment. A fourth brother with symptoms in infancy now has normal esophageal manometry findings. These boys in all likelihood have an X-linked syndrome with manifestations of FG syndrome, in which treatment with calcium channel blockers, produces clinical and manometric improvement. The FG syndrome is an X-linked syndrome of multiple congenital anomalies/mental retardation with facultative manifestations of gastrointestinal dysmotility, including gastro-esophageal reflux, severe feeding difficulties, and constipation. Esophageal dysmotility, in particular "nutcracker esophagus," should be suspected in infants with the FG syndrome and screaming attacks.     

The neurofaciodigitorenal (NFDR) syndrome

We describe in two brothers a previously apparently unreported multiple congenital anomalies/mental retardation (MCA/MR) syndrome of high, prominent forehead, vertical groove on tip of nose, “cowlick,” ear anomalies, acrorenal field defect (incipient unilateral triphalangism, broad halluces, with unilateral renal agenesis in one of the boys), megalencephaly associated with congenital hypotonia, severe mental retardation and highly abnormal EEG without seizures, intrauterine growth retardation and primordial shortness of stature in one brother. This is a Group III (“provisionally private”) MCA/MR syndrome and presumed to be due to a Mendelian (either X-linked or autosomal recessive) mutation. We do not think these patients have the FG syndrome. The condition has been named the neurofaciodigitorenal (NFDR) syndrome.     

Esophageal dysmotility in brothers with an FG‐like syndrome

We present 4 brothers with developmental delay, minor anomalies, and symptoms due to gastrointestinal dysmotility. There was some resemblance with FG syndrome, although none of the brothers had sufficient findings to make this diagnosis. The index case presented with at age 1 month with screaming episodes, mild gastro‐esophageal reflux (GER), and severe constipation. Esophageal manometry studies were consistent with the diagnosis of “nutcracker esophagus.” Symptomatic and manometric improvement followed treatment with oral calcium channel blockers. Two older and less severely affected brothers had similar manometric findings but did not require treatment. A fourth brother with symptoms in infancy now has normal esophageal manometry findings. These boys in all likelihood have an X‐linked syndrome with manifestations of FG syndrome, in which treatment with calcium channel blockers, produces clinical and manometric improvement. The FG syndrome is an X‐linked syndrome of multiple congenital anomalies/mental retardation with facultative manifestations of gastrointestinal dysmotility, including gastro‐esophageal reflux, severe feeding difficulties, and constipation. Esophageal dysmotility, in particular “nutcracker esophagus,” should be suspected in infants with the FG syndrome and screaming attacks. Am. J. Med. Genet. 91:185–189, 2000. © 2000 Wiley‐Liss, Inc.     

MICRO syndrome: an entity distinct from COFS syndrome

Children born with the findings of microcephaly, cataracts and microcornea can result not only from a prenatal viral infection, but also from an autosomal recessive Mendelian disorders. We present three pairs of affected siblings with MICRO syndrome, who were born with congenital microcephaly, microcornea, and cataracts. MICRO syndrome is an autosomal recessive syndrome consisting of congenital microcephaly, cortical dysplasia, microcornea, cataracts, optic atrophy, severe mental retardation, hypotonic diplegia, and hypogenitalism. At birth, MICRO syndrome resembles Cerebro-Oculo-Facio-Skeletal (COFS) syndrome, but it differs in the lack of the rapidly progressive neurologic features leading to severe brain atrophy with calcifications. Patients with MICRO syndrome manifest frontal cortical dysplasia, hypoplasia of the corpus callosum, cortical blindness with optic atrophy, profound mental retardation, and progressive joint contractures with growth failure. COFS syndrome shares also many clinical and cellular similarities with Cockayne syndrome (CS), and cultured cells in both conditions demonstrate hypersensitivity to ultraviolet (UV) radiation due to impaired nucleotide excision repair (NER). NER studies in cultured fibroblasts from MICRO patients give normal results, so MICRO syndrome should be considered in children with features resembling COFS syndrome and CS, but who have normal NER. MICRO should be distinguished from other similar clinical disorders with normal NER by the presence of significant visual impairment and cortical blindness despite early surgery for congenital cataracts, frontal polymicrogyria, thin corpus callosum, and cortical atrophy by MRI.     

A new X-linked syndrome with agenesis of the corpus callosum, mental retardation, coloboma, micrognathia, and a mutation in the Alpha 4 gene at Xq13

We describe two brothers with a unique pattern of malformations that includes coloboma (iris, optic nerve), high forehead, severe retrognathia, mental retardation, and agenesis of the corpus callosum (ACC). Both boys have low-set cupped ears with sensorineural hearing loss, normal phallus, pectus excavatum, scoliosis, and short stature. One brother had choanal atresia and cardiac defects consisting of ventricular septal defect (VSD) and patent ductus arteriosus (PDA) which resolved spontaneously. Differential diagnosis between a number of clinical entities was considered, however, because ACC and the distinctive facial features were reminiscent of FG syndrome, DNA was analyzed for markers linked to the FGS1 locus at Xq13-q21. Notably, the brothers were concordant for markers spanning this presumed FG region, and in both we have identified adjacent alterations (-57delT and T-55A) in the Alpha 4 gene located within this interval. Alpha 4 is a regulatory subunit of the major cellular phosphatase, PP2A, that has recently been shown to interact with MID1, the product of the gene mutated in X-linked Opitz GBBB syndrome. The double nucleotide change identified in this family was not observed in 410 control chromosomes, suggesting that it may be a pathogenetic change. Altered expression of Alpha 4, through either a change in translational efficiency, mRNA stability or splicing, could explain the clinical phenotype in these boys and the phenotypic overlap with Opitz GBBB syndrome.     

Syndrome of microcephaly, microphthalmia, cataracts, and intracranial calcification.

We present two sisters with microcephaly, developmental delay, marked microphthalmia, congenital cataracts, cerebral and cerebellar hypoplasia, and intracranial calcification. No evidence of intrauterine infection was found. There have been previous reports of microcephaly, intracranial calcification, and an intrauterine infection-like autosomal recessive condition, but the sibs in this report appear to represent a more severe form of such a condition or a previously undescribed entity.     

Lethal congenital muscular dystrophy with cataracts and a minor brain anomaly: new entity or variant of Walker-Warburg syndrome?

A term newborn male with severe hypotonia and contractures was found to have dense bilateral cataracts. He died at age 3 days of respiratory failure. Amino acidopathies and disorders of peroxisome function were excluded, and results of serologic studies and placental histopathology, specifically seeking evidence of intrauterine infection, were normal. Autopsy showed changes in the skeletal muscles consistent with congenital muscular dystrophy and a small focal anomaly of the cerebral cortex. These findings either represent a new syndrome or raise further questions about broadening the spectrum of known congenital muscular dystrophy syndromes with associated eye and brain anomalies.     

Cytomegalovirus infection in infants with autoimmune lymphoproliferative syndrome (ALPS)

Fas-mediated apoptosis may be one of the effector pathways leading to the elimination of virus-infected cells. Cytomegalovirus (CMV) infection in two brothers with Fas deficiency associated with autoimmunity and benign lymphoproliferation (ALPS) provided a unique opportunity to study the clinical course of CMV infection in children with defective apoptosis. The clinical courses of two brothers with autosomal dominant ALPS who were infected with CMV in the neonatal period are described. CMV was detected from throat and urine culture from the brothers. ALPS was confirmed by in vitro anti-CD95 MoAb-induced T lymphocyte apoptosis assay and subsequent sequencing and identification of mutations in the Fas gene. A de novo mutation in the Fas gene, leading to a truncated cytoplasmic Fas product, was associated with autosomal dominant ALPS in a mother and her two sons. Both boys had evidence of CMV infection acquired early in infancy which cleared by the age of 2-3 years. There were no neurodevelopmental sequelae. The natural history of CMV infection in two infants with ALPS was similar to that described in normal children.     

A new X linked syndrome with mental retardation and craniofacial dysmorphism?

We present a syndrome manifested in two half brothers and their two maternal aunts which is characterised in the two boys by severe mental retardation and craniofacial dysmorphism (broad, coarse features and marked plagiocephaly with flattened occiput), and in the aunts merely by moderate mental retardation without dysmorphic features. The brothers do not seem to fall into any previously described X linked syndrome with mental retardation.     

Two brothers with heart defects and limb shortening: case reports and review.

Two male Arab sibs are reported with congenital heart disease and skeletal malformations. Other published case reports sharing some features in common with these brothers are considered. However, clinical and radiological features in these boys are distinct enough to represent a new cardioskeletal syndrome.     

Syndrome of microcephaly,microphthalmia, cataracts,and intracranial calcification

We present two sisters with microcephaly, developmental delay, marked microphthalmia, congenital cataracts, cerebral and cerebellar hypoplasia, and intracranial calcification. No evidence of intrauterine infection was found. There have been previous reports of microcephaly, intracranial calcification, and an intrauterine infection-like autosomal recessive condition, but the sibs in this report appear to represent a more severe form of such a condition or a previously undescribed entity. Am. J. Med. Genet. 84:330–333, 1999. © 1999 Wiley-Liss, Inc.     

Neonatal progeroid syndrome: more than one disease?

We report on an infant with the neonatal progeroid syndrome whose clinical course and autopsy findings indicate that this may be a heterogeneous phenotype. The infant had intrauterine growth retardation, absence of subcutaneous fat, and a wizened, aged face, all apparently characteristic of the condition, but also had congenital heart defects and urinary reflux not reported in previous cases. An elevated maternal serum alpha fetoprotein was noted at 16 weeks of gestation and late-onset growth retardation appeared after 31 weeks. Autopsy findings showed normal cerebral myelination, in contrast to findings of sudanophilic leukodystrophy in the one patient with the syndrome previously examined at autopsy. These findings suggest that the neonatal progeroid syndrome may be a phenotype and have more than one cause.     

Sotos syndrome in two brothers

Two brothers presented from birth with features characteristic of Sotos syndrome (cerebral gigantism): overgrowth, craniofacial abnormalities, and mental retardation with hyperactive and aggressive behavior. X-ray examination of the hands revealed imbalanced and advanced skeletal age in one, whereas anterior fontanel bones were present in both brothers. Various hormone concentrations in plasma were all within normal limits, as were the results of a search for abnormal metabolites in plasma and urine. The occurrence of this usually sporadic syndrome in two sons of possibly remotely consanguineous, healthy parents, suggests that in some cases Sotos syndrome may be inherited as an autosomal recessive trait. Thus our observation may support the suggestion of heterogeneity of Sotos syndrome. Until specific tests for the identification of various types are available, genetic counseling for this syndrome is difficult.     

The Bowen-Conradi syndrome -- a highly lethal autosomal recessive syndrome of microcephaly, micrognathia, low birth weight, and joint deformities.

This paper describes six Hutterite children from five families who appear to have been affected by the same syndrome that was described in two brothers by Bowen and Conradi [1]. Our additional cases confirm that the major features of the syndrome include porportionate intrauterine growth retardation, microcephaly, micrognathia, a prominent nose, rocker-bottom feet, joint limitation, and failure to thrive, with death within the first year of life. Bowen-Conradi syndrome is an autosomal recessive trait and pedigree records show that all six families now known are related to each other through two couples born in the late 1700s but that there are additional earlier possible sources of the responsible gene. The differential diagnosis of this syndrome is discussed.     

Two brothers with macrocephaly, progressive cerebral atrophy and abnormal white matter, severe mental retardation, and Lennox-Gastaut spectrum type epilepsy: an inherited encephalopathy of childhood?

Two brothers with severe mental retardation of unknown origin were found to share several physical anomalies, including large round head, small concave nose, downslanted palpebral fissures, and gingival hyperplasia. In addition to relative macrocephaly, magnetic resonance imaging (MRI) showed severe cerebral atrophy, especially fronto-temporally. The brothers also had a thin corpus callosum and atrophic caudate nuclei. The reduced white matter showed patchy periventricular signal intensity changes. The lateral and third ventricles were large, but the fourth ventricle was of normal size. The boys had large cisterna magna, communicating widely with the fourth ventricle, but no vermian hypoplasia. Both boys had Lennox-Gastaut spectrum type epilepsy. No chromosomal anomalies were found, despite the suggestive clinical picture. Some of the clinical findings resembled fetal alcohol effects/fetal alcohol syndrome (FAE/FAS), which was also suggested by history. Current diagnostic criteria for FAE/FAS, however, excluded full-blown FAS in these cases and failed to explain the entire clinical picture in the boys. We argue that these boys had an unidentified inherited syndrome, possibly modified by fetal alcohol exposure.     

Autosomal recessive Robinow syndrome

Two brothers of normal first-cousin parents were found to have Robinow syndrome. Their paternal uncle also married a first cousin and had 3 similarly affected children (2 boys, 1 girl). The 2 affected brothers had short stature, mesomelic and acromelic brachymelia, characteristic face with hypertelorism, wide palpebral fissures, midface hypoplasia and large mouth, and hypogenitalism. Parental consanguinity and affected individuals in 2 sibships of common ancestry strongly suggest autosomal recessive inheritance. Similar cases from the literature are briefly reviewed.     

Genital anomaly and cardiomyopathy: a new syndrome

Two brothers, products of a consanguineous marriage, had severe hypoplastic genitalia and cardiomyopathy. These findings are similar to those of three other brothers of another consanguineous family who in addition had evidence of mental retardation. These five boys probably represent a previously undescribed syndrome of genetic origin but of poorly understood pathogenesis.     

Unusual renal features of Lowe syndrome in a mildly affected boy

The oculocerebrorenal syndrome of Lowe (OCRL) is an X-linked disorder characterized by congenital cataracts, mental retardation, and renal tubular dysfunction. The gene responsible for OCRL was identified by positional cloning and encodes a lipid phosphatase, phosphatidylinositol 4,5, bisphosphate [PtdIns(4,5)P2]5-phosphatase, which localizes to the Golgi apparatus and is suspected to play a role in Golgi vesicular transport [Suchy et al., 1995]. In addition to the ocular and renal manifestations, most boys with OCRL have cognitive problems and maladaptive behaviors including tantrums and stereotypies. We report a boy with a history of congenital cataracts and mild developmental delay who was also found to have hematuria with proteinuria but minimal signs of renal tubular dysfunction. Subsequent renal biopsy was compatible with a diagnosis of a noncomplement fixating chronic glomerulonephritis. Despite the atypical renal findings, skin fibroblast analysis for PtdIns (4,5)P2 5-phosphatase was performed, and enzyme activity was low, consistent with the diagnosis of OCRL. Western blot analysis from cell lysates showed the ocrl protein was decreased in size and amount. Our report shows atypical renal features of OCRL in a mildly affected boy. The possibility of OCRL should be considered in boys with cataracts and glomerular disease, even in the absence of renal tubular defects and frank mental retardation usually associated with the syndrome. Am. J. Med. Genet. 95:461-466, 2000. Published Wiley-Liss, Inc.     

Mohr syndrome (oro-facial-digital syndrome II) - a familial case with different phenotypic findings

We report on two male siblings with an oro-facial-digital syndrome. The parents and two other siblings, a boy and a girl, are unaffected. The clinical findings on the reported brothers were different. Patient 1 had typical oral, facial and digital anomalies plus hypoplastic genitalia and short limbs. Clinically he had marked hypotonia, convulsions and apneic episodes. He died shortly after birth. His brother, Patient 2, had OFD features with conductive hearing loss and normal psychomental development. He did not have syndactylous reduplication of the great toes, although the toes were disproportionately large. These two patients are classified as OFD type II-Mohr syndrome. Involvement of the central nervous system in OFD type II is noted. Different phenotypic findings could be explained as variable gene expressivity. The patients described here support the hypothesis that the clinical variability of the Mohr syndrome is even wider than previously thought.