The X-linked syndrome of macroorchidism and mental retardation: further observations.

We report six males with the syndrome of macroorchidism and mental retardation. The trait is inherited as though X-linked, or possibly autosomal dominant male-limited. We also found no evidence of gonadal dysfunction. Associated abnormalities were abnormal EEG (3/4), seizures (2/6), and one instance each of cervical vertebral fusion, cataract, esophoria, and abnormal cutaneous pigmentation. One woman with a 50% a priori risk of bearing the mutant gene had mental retardation and seizures. Results of Xg blood-group typing were uninformative for the purpose of linkage analysis.     

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.     

The X-linked syndrome of macroorchidism and mental retardation: Further observations

We report six males with the syndrome of macroorchidism and mental retardation. The trait is inherited as though X-linked, or possibly autosomal dominant male-limited. We also found no evidence of gonadal dysfunction. Associated abnormalities were abnormal EEG (3/4), seizures (2/6), and one instance each of cervical vertebral fusion, cataract, esophoria, and abnormal cutaneous pigmentation. One woman with a 50% a priori risk of bearing the mutant gene had mental retardation and seizures. Results of Xg blood-group typing were uninformative for the purpose of linkage analysis.     

Syndrome of gingival hypertrophy, hirsutism, mental retardation and brachymetacarpia in two sisters: specific entity or variant of a described condition?

Two sisters born to consanguineous Lebanese parents had mental retardation and epilepsy, brachymetacarpalia, hirsutism, bulbous soft nose, thick floppy ears with abnormal configuration and gingival hypertrophy. One girl presented additionally with tetralogy of Fallot and the other with congenital hypothyroidism and bilateral ureteral stenosis. These manifestations resemble the syndrome of hypertrichosis-gingival fibromatosis-mental retardation and seizures of Anavi et al. [1989: Dev Med Child Neurol 31:538-542] but our two girls additionally have brachymetacarpia. The inheritance seems to be autosomal recessive. These two sisters may represent a hitherto undescribed syndrome. We discuss the findings in our patients in relation to the literature.     

The clinical atlas of Greig cephalopolysyndactyly syndrome

Greig cephalopolysyndactyly syndrome (GCPS) is a rare multiple congenital anomaly syndrome that is inherited in an autosomal dominant pattern and is caused by haploinsufficiency of the GLI3 gene. The syndrome typically includes preaxial or mixed pre- and postaxial polydactyly and cutaneous syndactyly, ocular hypertelorism, and macrocephaly in its typical forms, but sometimes includes hydrocephalus, seizures, mental retardation, and developmental delay in more severe cases. Patients with milder forms of GCPS can have subtle craniofacial dysmorphic features that are difficult to distinguish from normal variation. This article presents the spectrum of dysmorphic findings in GCPS highlighting some of its key presenting features to familiarize clinicians with the variable expressivity of the condition.     

Reply to Dr. Winter

Although Costello syndrome is considered to be an autosomal recessive disorder, review of 20 families demonstrated that the 37 sibs of the probands were all normal. In 6 families on whom pedigrees were not available, 2 affected sib-pairs were born. Even if there were no normal offspring in these latter families, the occurrence of the Costello syndrome in only 2 of 39 sibs virtually excludes an autosomal recessive inheritance pattern (P = 0.999). Moreover, a significant increase of mean paternal age (38.0 yr) and paternal-maternal age difference (7.36 yr) suggests sporadic autosomal dominant mutations as a likely cause. The 2 reported cases of affected sibs born to healthy parents may be explained by gonadal mosaicism, although heterogeneity with a small proportion of recessively inherited cases cannot be excluded. © 1994 Wiley-Liss, Inc.     

Coffin-Lowry syndrome: a multicenter study

The Coffin-Lowry syndrome is an inherited syndrome of mental retardation, characteristic facies and skeletal anomalies. The occurrence of severe manifestations in males, with no instance of male-to-male transmission, suggests an X-linked inheritance. The paper describes seven families from five European Centers.     

Yellow teeth, seizures, and mental retardation: a less severe case of Kohlschütter-Tönz syndrome

We describe an 11-year-old boy with hypoplastic amelogenesis imperfecta, yellow teeth, seizures, and developmental delay, which are the hallmarks of Kohlschütter-T?nz syndrome. Compared to other reported cases of the syndrome, our patient had less severe developmental delay. Also, spasticity and loss of mental capacity should not be considered obligatory manifestations of the syndrome because they are not present in half of reported patients, as well as in our family. Origin of the parents of our patient from neighboring villages supports autosomal recessive inheritance of Kohlschütter-T?nz syndrome.     

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.     

Prader-Willi syndrome in a brother and sister without cytogenetic or detectable molecular genetic abnormality at chromosome 15q11q13

We report on a 12-year-old boy and his 7-year-old sister with the Prader-Willi syndrome. They both had severe initial hypotonia with feeding problems and later developed an increasing appetite. Both sibs have almond-shaped eyes, triangular mouth, hypogonadism, retarded growth, and mental retardation. An older brother suffered from severe hypotonia and died at 7 days of age. The children have normal chromosomes by high-resolution technique and have inherited the same chromosomes 15 short arm polymorphisms from their parents. The family was informative for one of four DNA markers specific for the 15q11q13 region. No deletion was found using this marker. The parents were healthy and unrelated. Autosomal recessive inheritance or a paternally inherited submicroscopic deletion are possible explanations for the sib occurrence in this family. © Wiley-Liss, Inc.     

Prader-Willi syndrome in a brother and sister without cytogenetic or detectable molecular genetic abnormality at chromosome 15q11q13.

We report on a 12-year-old boy and his 7-year-old sister with the Prader-Willi syndrome. They both had severe initial hypotonia with feeding problems and later developed an increasing appetite. Both sibs have almond-shaped eyes, triangular mouth, hypogonadism, retarded growth, and mental retardation. An older brother suffered from severe hypotonia and died at 7 days of age. The children have normal chromosomes by high-resolution technique and have inherited the same chromosomes 15 short arm polymorphisms from their parents. The family was informative for one of four DNA markers specific for the 15q11q13 region. No deletion was found using this marker. The parents were healthy and unrelated. Autosomal recessive inheritance or a paternally inherited submicroscopic deletion are possible explanations for the sib occurrence in this family.     

Gonadal mosaicism as a rare cause of autosomal recessive inheritance

Autosomal recessive diseases are typically caused by the biparental inheritance of familial mutant alleles. Unusual mechanisms by which the recessiveness of a mutant allele is unmasked include uniparental isodisomy and the occurrence of a de novo chromosomal rearrangement that disrupts the other allele. Gonadal mosaicism is a condition in which a postfertilization mutation is confined to the gamete precursors and is not detected in somatic tissues. Gonadal mosaicism is known to give the impression of autosomal recessive inheritance when recurrence of an autosomal‐dominant condition among offspring of phenotypically normal parents is observed. Here, we report an extremely rare event in which maternal gonadal mosaicism for a recessive mutation in COL4A4 caused the recurrence of Alport syndrome within a consanguineous family. Such rare occurrence should be taken into account when analyzing pedigrees both for clinical and research purposes.     

Autosomal recessive intestinal lymphangiectasia and lymphedema, with facial anomalies and mental retardation

We report on two male and two female relatives with intestinal lymphangiectasia; severe lymphedema of limbs, genitalia, and face; facial anomalies; seizures; mild growth retardation; and moderate mental retardation. Main facial anomalies are a flat face, flat nasal bridge, hypertelorism, small mouth, tooth anomalies, and ear defects. Their parents are consanguineous. This disorder probably is an hitherto undescribed autosomal recessive syndrome.     

Revisiting metatropic dysplasia: presentation of a series of 19 novel patients and review of the literature

Metatropic dysplasia (MD-OMIM: 156530 and 250600) is a rare chondrodysplasia characterized by short limbs with limitation and enlargement of joints and usually severe kyphoscoliosis, first described in 1893. Up until now, 81 other patients have been reported. The phenotypic variability of MD has led to a classification based on radiological anomalies dividing into three different types: a lethal autosomal recessive form, an autosomal recessive non-lethal form and a non-lethal autosomal dominant form with less severe radiographs manifestations and a better clinical outcome. Here, we report on clinical and radiological features of 19 novel MD patients. We describe new radiological features, including precocious calcification of hyoid and cricoid cartilage, irregular and squared-off calcaneal bones and severe hypoplasia of the anterior portion of first cervical vertebrae. In addition, the observation of an overlap between the autosomal recessive non-lethal form and the non-lethal autosomal dominant form, the rarity of sibship recurrences and the observation of vertical transmissions of MD in the literature argue in favor of an autosomal dominant mode of inheritance for all MD types. This hypothesis is reinforced by the use of the statistical single ascertainment method that rejects the hypothesis of an autosomal recessive mode of inheritance responsible for MD. Therefore, we propose that recurrence in sibs is due to gonadal mosaicism.     

Cleft palate-lateral synechiae syndrome: Report on three new patients with additional findings and evidence for variability and heterogeneity

We report on 3 Brazilian children with short stature, microcephaly, cleft palate, lateral synechiae, and mild mental retardation. One patient was an isolated case and the other had an equally affected brother. Genetic aspects and phenotypic manifestations are compared with those of previous reports with oral synechiae. Recurrence in sibs suggests autosomal recessive inheritance. © 1993 Wiley-Liss, Inc.     

The syndrome of retinal pigmentary degeneration, microcephaly, and severe mental retardation (Mirhosseini-Holmes-Walton syndrome): report of two patients

We report on two daughters, born to consanguineous parents, who had severe mental retardation, microcephaly, retinal pigmentary degeneration, and spastic cerebral palsy. We think that this syndrome is the same as that described by Mirhosseini et al [1972] (McK-26805). The presence of consanguinity favors the hypothesis of autosomal recessive inheritance.     

Angelman syndrome resulting from UBE3A mutations in 14 patients from eight families: clinical manifestations and genetic counselling

Angelman syndrome (AS) is a neurological disorder with a heterogeneous genetic aetiology. It most frequently results from a de novo interstitial deletion in the 15q11-q13 region, but in a few cases it is caused by paternal uniparental disomy (UPD) or an imprinting mutation. The remaining 20 to 30% of AS patients exhibit biparental inheritance and a normal pattern of allelic methylation in the 15q11-q13 region. In this latter group, mutations in the UBE3A gene have recently been shown to be a cause of AS. Here we describe the phenotypic expression in 14 AS cases involving eight UBE3A mutations. These comprise 11 familial cases from five families and three sporadic cases. Subtle differences from the typical phenotype of AS were found. Consistent manifestations were psychomotor delay, a happy disposition, a hyperexcitable personality, EEG abnormalities, and mental retardation with severe speech impairment. The other main manifestations of AS, ataxia, epilepsy, and microcephaly, were either milder or absent in various combinations among the patients. In addition, myoclonus of cortical origin was frequently observed with severe fits inducing myoclonic seizures. The majority of the patients were overweight. This study showed that ataxia, myoclonus, EEG abnormalities, speech impairment, characteristic behavioural phenotype, and abnormal head circumference are attributable to a deficiency in the maternally inherited UBE3A allele. Furthermore, analysis of mutation transmission showed an unexpectedly high rate of somatic mosaicism in normal carriers. These data have important consequences for genetic counselling.     

Microcephaly with simplified gyral pattern in six related children.

We describe clinical and neurophysiological findings in six related children with congenital microcephaly, seizures that began within the first 2-4 months of life, and severe mental retardation (MR). These affected children (five girls and one boy), born to two women who are half-sisters, inherited the disease as an autosomal recessive trait. Physical examination of these children did not show any of the anomalies in the known cortical malformation syndromes such as lissencephaly types I and II. Neuroradiological studies in these children documented microcephaly and a simplified gyral pattern with no pachygyria. Chromosomal analysis showed neither karyotypic abnormalities nor a microdeletion at 17p13.3, site of the lissencephaly type I gene locus (LIS1). Genetic studies failed to show linkage of this family to LIS1, LIS2 (a region on chromosome 2p homologous to LIS1), or MCPH1 (a locus for primary autosomal recessive microcephaly). The unique clinical and genetic findings in this family suggest that these children may be affected by an as-of-yet unmapped neuronal proliferation disorder.     

Syndrome of microcephaly, Dandy-Walker malformation, and Wilms tumor caused by mosaic variegated aneuploidy with premature centromere division (PCD): report of a new case and review of the literature

We report a male infant with multiple congenital anomalies and mosaic variegated aneuploidy; a rare cytogenetic abnormality characterized by mosaicism for several different aneuploidies involving many different chromosomes. He had prenatal-onset growth retardation, microcephaly, dysmorphic face, seizures, hypotonia, feeding difficulty, and developmental delay. In addition, he developed bilateral Wilms tumors. Neuroradiological examination revealed Dandy-Walker malformation and hypoplasia of the cerebral hemisphere and pons. Cytogenetic analysis revealed various multiple numerical aneuploidies in blood lymphocytes, fibroblasts, and bone marrow cells, together with premature centromere division (PCD). Peripheral blood chromosome analysis from his parents also showed PCD, but no aneuploid cells. The clinical phenotype and multiple aneuploidies of the patient may be a consequence of the homozygous PCD trait inherited from his parents. Comparison with previously reported cases of multiple aneuploidy suggests that mosaic variegated aneuploidy with PCD may be a clinically recognizable syndrome with major phenotypes being mental retardation, microcephaly, structural brain anomalies (including Dandy-Walker malformation), and possible cancer predisposition. Received: January 21, 1999 / Accepted: February 26, 1999