Subtelomeric deletions of chromosome 6p: molecular and cytogenetic characterization of three new cases with phenotypic overlap with Ritscher-Schinzel (3C) syndrome

We have identified six children in three families with subtelomeric deletions of 6p25 and a recognizable phenotype consisting of ptosis, posterior embryotoxon, optic nerve abnormalities, mild glaucoma, Dandy-Walker malformation, hydrocephalus, atrial septal defect, patent ductus arteriosus, and mild mental retardation. There is considerable clinical overlap between these children and individuals with the Ritscher-Schinzel (or cranio-cerebello-cardiac (3C)) syndrome (OMIM #220210). Clinical features of 3C syndrome include craniofacial anomalies (macrocephaly, prominent forehead and occiput, foramina parietalia, hypertelorism, down-slanting palpebral fissures, ocular colobomas, depressed nasal bridge, narrow or cleft palate, and low-set ears), cerebellar malformations (variable manifestations of a Dandy-Walker malformation with moderate mental retardation), and cardiac defects (primarily septal defects). Since the original report, over 25 patients with 3C syndrome have been reported. Recessive inheritance has been postulated based on recurrence in siblings born to unaffected parents and parental consanguinity in two familial cases. Molecular and cytogenetic mapping of the 6p deletions in these three families with subtelomeric deletions of chromosome 6p have defined a 1.3 Mb minimally deleted critical region. To determine if 6p deletions are common in 3C syndrome, we analyzed seven unrelated individuals with 3C syndrome for deletions of this region. Three forkhead genes (FOXF1 and FOXQ1 from within the critical region, and FOXC1 proximal to this region) were evaluated as potential candidate disease genes for this disorder. No deletions or disease-causing mutations were identified.     

Cowden syndrome.

Cowden syndrome, or the multiple hamartoma syndrome, is a familial cancer syndrome with involvement of various organ systems. Inheritance is autosomal dominant with variable expression. Progressive macrocephaly, scrotal tongue, and mild to moderate mental retardation are important signs indicating the syndrome in young children. Other mucocutaneous symptoms, for example, trichilemmomas in the nasolabial folds and palmar and plantar hyperkeratotic pits, usually become evident later in childhood. They are often accompanied by the appearance of subcutaneous lipomas and cutaneous haemangiomas.     

A new lipid storage myopathy observed in individuals with the Ruvalcaba-Myhre-Smith syndrome

Four patients with the Ruvalcaba-Myhre-Smith syndrome (primary macrocephaly with associated anomalies including pigmented macules on the penis in affected males, hamartomatous intestinal polyps, and lipomas) had evidence of delayed psychomotor development and/or hypotonia in childhood. Electromyography in 3 patients showed evidence of a myopathic process. Muscle biopsy in all four demonstrated a lipid storage myopathy with increased numbers of neutral lipid droplets--predominatly in type 1 fibers. The type 2 fibers were consistently smaller than expected. Electron microscopy was unremarkable except for evidence of lipid accumulation. Muscle carnitine and carnitine palmityl transferase levels were normal in one patient. This appears to be a previously unreported type of lipid storage myopathy characteristic of the Ruvalcaba-Myhre-Smith syndrome, a probable autosomal dominant trait.     

Mutations of PTEN in patients with Bannayan-Riley-Ruvalcaba phenotype.

We report three new mutations in PTEN, the gene responsible for Cowden disease in five patients with Bannayan-Riley-Ruvalcaba syndrome from three unrelated families. This finding confirms that Cowden disease, a dominant cancer predisposing syndrome, and Bannayan-Riley-Ruvalcaba syndrome, which includes macrocephaly, multiple lipomas, intestinal hamartomatous polyps, vascular malformations, and pigmented macules of the penis, are allelic disorders at the PTEN locus on chromosome 10q.     

PTEN mutation spectrum and genotype-phenotype correlations in Bannayan-Riley-Ruvalcaba syndrome suggest a single entity with Cowden syndrome.

Germline mutations in the tumour suppressor gene PTEN have been implicated in two hamartoma syndromes that exhibit some clinical overlap, Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRR). PTEN maps to 10q23 and encodes a dual specificity phosphatase, a substrate of which is phosphatidylinositol 3,4,5-triphosphate, a phospholipid in the phosphatidylinositol 3-kinase pathway. CS is characterized by multiple hamartomas and an increased risk of benign and malignant disease of the breast, thyroid and central nervous system, whilst the presence of cancer has not been formally documented in BRR. The partial clinical overlap in these two syndromes is exemplified by the hallmark features of BRR: macrocephaly and multiple lipomas, the latter of which occur in a minority of individuals with CS. Additional features observed in BRR, which may also occur in a minority of CS patients, include Hashimoto's thyroiditis, vascular malformations and mental retardation. Pigmented macules of the glans penis, delayed motor development and neonatal or infant onset are noted only in BRR. In this study, constitutive DNA samples from 43 BRR individuals comprising 16 sporadic and 27 familial cases, 11 of which were families with both CS and BRR, were screened for PTEN mutations. Mutations were identified in 26 of 43 (60%) BRR cases. Genotype-phenotype analyses within the BRR group suggested a number of correlations, including the association of PTEN mutation and cancer or breast fibroadenoma in any given CS, BRR or BRR/CS overlap family ( P = 0.014), and, in particular, truncating mutations were associated with the presence of cancer and breast fibroadenoma in a given family ( P = 0.024). Additionally, the presence of lipomas was correlated with the presence of PTEN mutation in BRR patients ( P = 0.028). In contrast to a prior report, no significant difference in mutation status was found in familial versus sporadic cases of BRR ( P = 0.113). Comparisons between BRR and a previously studied group of 37 CS families suggested an increased likelihood of identifying a germline PTEN mutation in families with either CS alone or both CS and BRR when compared with BRR alone ( P = 0.002). Among CS, BRR and BRR/CS overlap families that are PTEN mutation positive, the mutation spectra appear similar. Thus, PTEN mutation-positive CS and BRR may be different presentations of a single syndrome and, hence, both should receive equal attention with respect to cancer surveillance.     

Long-chain 3-hydroxyacyl-Coenzyme A dehydrogenase (L-CHAD) deficiency in a patient with the Bannayan-Riley-Ruvalcaba syndrome

Bannayan-Riley-Ruvalcaba syndrome (BRRS) is an autosomal dominant condition of macrocephaly in combination with lipomas/hemangiomas, hypotonia, developmental delay, and a lipid myopathy. The etiology of the lipid storage myopathy has been unclear. We describe a black boy with findings of BRRS who also has a defect in long-chain fatty acid oxidation expressed in cultured skin fibroblasts as a deficiency of long-chain-L-3-hydroxyacyl-CoA dehydrogenase (L-CHAD). He also has an abnormal brain MRI and increased size of both lower limbs. We present this child because of his unusual combination of findings, and postulate that L-CHAD deficiency may be the cause of the lipid myopathy in BRRS. © 1994 Wiley-Liss, Inc.     

Multiple congenital anomalies/mental retardation (MCA/MR) syndrome due to partial 1q duplication and possible 18p deletion: a study of four individuals in two families.

We have evaluated four individuals from two unrelated families with a similar multiple congenital anomalies/mental retardation (MCA/MR) syndrome due to partial duplication of chromosome 1q and possible deletion 18p. In both families the mothers and several relatives were carriers of the balanced translocation rcp t(1;18) (q42;p11). The features which the four have in common are relative macrocephaly, prominent forehead, micrognathia, and highly arched palate; three of the four individuals have short stature, scoliosis, kyphosis, hirsutism, camptodactyly, sacral dimple, repaired inguinal hernias, and eye abnormalities. Reproductive histories of five balanced translocation carriers in these families indicate that they have a high risk of spontaneous abortions and infants with multiple malformations.     

Genetic mapping of a novel familial form of infantile hemangioma

Infantile hemangiomas are the most common tumor of infancy, occurring with an incidence of up to 10% of all births. They are benign but highly proliferative lesions involving aberrant localized growth of capillary endothelium. Although most hemangiomas occur sporadically and as single lesions, or in conjunction with pleiotropic genetic syndromes, we have previously identified six kindreds where hemangiomas appear to segregate as an autosomal dominant trait with high penetrance. Four such families contain affected individuals in three or more generations. In the current study, blood samples from five of these families were collected and used in a whole genome linkage search at 10-cM resolution. We established evidence for linkage to 5q in three families, and evidence for locus heterogeneity. The three 5q-linked families were further genotyped to generate haplotype information and narrow the candidate interval. Based on recombination breakpoint analysis, the interval exists between markers D5S2490 and D5S408, spanning 55 cM, and corresponding to 5q31-33. Using information from affected and uaffected individuals, the interval spans 38 cM between markers D5S1469 and D5S211. Three candidate genes involved with blood vessel growth map to this region: fibroblast growth factor receptor-4 (FGFR4), platelet-derived growth factor receptor-beta (PDGFRB), and fms-related tyrosine kinase-4 (FLT4). The genes and gene products associated with familial hemangiomas may be involved somatically in the more common sporadic cases. Am. J. Med. Genet. 82:77–83, 1999. © 1999 Wiley-Liss, Inc.     

Mutation screening of all 65 exons of the fibrillin-1 gene in 60 patients with Marfan syndrome: Report of 12 novel mutations

Mutations in the fibrillin-1 gene on chromosome 15q21.1 have been found to cause Marfan syndrome, a dominantly inherited disorder characterised by clinically variable skeletal, ocular, and cardiovascular abnormalities. In this study we screened all 65 exons of the fibrillin-1 gene in 20 Marfan syndrome families where at least two affected individuals were characterised and available for analysis, another 30 families with only one affected member available for analysis, and in 10 sporadic cases. In large well-characterised families with more than four affected individuals, the detection rate for mutations rose to 78% (7/9), in families with either two or three affected members 27% (3/11). In families where only one affected family member was available, the mutation detection rate was 17% (5/30), and in sporadic cases it was 20% (2/10). In addition, we found eight neutral polymorphisms. Twelve of the 17 disease-causing mutations identified have not been previously described, thus raising the total number of different fibrillin-1 mutations reported to 85 in 94 unrelated cases. Hum Mutat 10:280–289, 1997. © 1997 Wiley-Liss, Inc.     

Testicular lipomatosis in Cowden's syndrome.

Cowden's syndrome is either familial or sporadic and is associated with the predominantly postpubertal development of a variety of cutaneous, stromal and visceral neoplasms. The syndrome is associated with mutations of the PTEN gene and is closely related to Bannayan's syndrome in which macrocephaly and benign tumors, especially lipomas and hemangiomas are pathognomic. In PTEN knockout mice testicular tumors have been reported and for this reason we felt it prudent to examine the testes of our patients with genetically proven Cowden's syndrome. Seven of eight patients who underwent testicular ultrasound were found to have diffuse bilateral hyperechoic lesions. Four patients consented to testicular biopsy and on histological examination multiple foci of adipocytes were found within the testicular interstitium, with no evidence of dysplasia or preclinical malignancy. Immunohistochemical assessment of adipocytes suggested a stromal derivation without evidence of metaplasia from Leydig cells. In one case there was focal atrophy of seminiferous tubules, while in two others there was nodular periorchitis of the tunica albuginea. Biochemical evaluation of testicular function (luteinizing hormone, follicle-stimulating hormone, testosterone, sex hormone binding globulin and free androgen index), prostate-specific antigen and testicular tumor markers were normal, while seminal fluid analysis showed only minor abnormalities. The high incidence of testicular lipomatosis in our adult subjects suggests this to be an important diagnostic criterion for Cowden's syndrome.     

Familial DiGeorge/velocardiofacial syndrome with deletions of chromosome area22q11.2: Report of five families with a review of the literature

The DiGeorge (DG), velocardiofacial (VCF), and conotruncal anomaly-face (CTAF) syndromes were originally described as distinct disorders, although overlapping phenotypes have been recognized. It is now clear that all three syndromes result from apparently similar or identical 22q11.2 deletions, suggesting that they represent phenotypic variability of a single genetic syndrome. We report on 12 individuals in five families with del(22)(q11.2) by fluorescent in situ hybridization, and define the frequency of phenotypic abnormalities in those cases and in 70 individuals from 27 del(22)(q11.2) families from the literature. Common manifestations include mental impairment (97%), abnormal face (93%), cardiac malformations (68%), thymic (64%) and parathyroid (63%) abnormalities, and cleft palate or velopharyngeal insufficiency (48%). Familial DG, VCF, and CTAF syndromes due to del(22)(q11.2) show significant inter- and intra-familial clinical variability consistent with the hypothesis that a single gene or group of tightly linked genes is the common cause of these syndromes. Up to 25% of 22q deletions are inherited, indicating that parents of affected children warrant molecular cytogenetic evaluation. We propose use of the compound term “DiGeorge/velocardiofacial (DG/VCF) syndrome” in referring to this condition, as it calls attention to the phenotypic spectrum using historically familiar names. © 1996 Wiley-Liss, Inc.     

Cowden syndrome: report of a large family with macrocephaly and increased severity of signs in subsequent generations

Hanssen AMN, Werquin H, Suys E, Fryns JP. Cowden syndrome: report of a large family with macrocephaly and increased severity of signs in subsequent generations.
Clin Genet 1993: 44: 281–286. © Munksgaard, 1993
We report Cowden syndrome in a large four-generation family, paying special attention to the apparently greater severity and earlier onset of signs and symptoms in subsequent generations. Macrocephaly was present in all affected individuals and was markedly progressive in three of six affected children of the fourth generation, and associated with slight to moderate delay in psychomotor development.     

Cardio-facio-cutaneous syndrome: Does genotype predict phenotype?

Cardio-facio-cutaneous (CFC) syndrome is a sporadic multiple congenital anomalies/mental retardation condition principally caused by mutations in BRAF, MEK1, and MEK2. Mutations in KRAS and SHOC2 lead to a phenotype with overlapping features. In approximately 10–30% of individuals with a clinical diagnosis of CFC, a mutation in one of these causative genes is not found. Cardinal features of CFC include congenital heart defects, a characteristic facial appearance, and ectodermal abnormalities. Additional features include failure to thrive with severe feeding problems, moderate to severe intellectual disability and short stature with relative macrocephaly. First described in 1986, more than 100 affected individuals are reported. Following the discovery of the causative genes, more information has emerged on the breadth of clinical features. Little, however, has been published on genotype–phenotype correlations. This clinical study of 186 children and young adults with mutation-proven CFC syndrome is the largest reported to date. BRAF mutations are documented in 140 individuals (approximately 75%), while 46 (approximately 25%) have a mutation in MEK 1 or MEK 2. The age range is 6 months to 32 years, the oldest individual being a female from the original report [Reynolds et al. (1986); Am J Med Genet 25:413–427]. While some clinical data on 136 are in the literature, 50 are not previously published. We provide new details of the breadth of phenotype and discuss the frequency of particular features in each genotypic group. Pulmonary stenosis is the only anomaly that demonstrates a statistically significant genotype–phenotype correlation, being more common in individuals with a BRAF mutation.     

A family with mental retardation, variable macrocephaly and macro-orchidism, and linkage to Xq12-q21.

A family with X linked inheritance of mental retardation (XLMR) is presented. There are 10 mentally retarded males and two affected females in two generations. There are four obligatory carriers, one of whom is described as "slow". Most affected males show macrocephaly and macro-orchidism, which are typical signs of the fragile X syndrome, but have been tested cytogenetically and by analysis of the FMR1 gene and do not have this syndrome. However, some normal males in the family also exhibit macro-orchidism and macrocephaly. Linkage analysis using markers derived from the X chromosome indicates that the causative gene in this family is located in the proximal long arm of the X chromosome, in the interval Xp11-q21. Maximum lod scores of 2.96 with no recombination were found at three loci in Xq13-q21: DXS1111, DXS566, and DXS986. Recombination was observed with DXS1002 (Xq21.31) and DXS991 (Xp11.2), loci separated by about 30 Mb. Although isolation of the gene in this family will be difficult because of the size of the region involved, the localisation should be helpful in investigating other similar families with XLMR, macrocephaly, and macro-orchidism not attributable to FMR1.     

Watson syndrome: is it a subtype of type 1 neurofibromatosis?

Over 20 years ago, Watson described three families with a condition characterised by pulmonary valvular stenosis, café au lait patches, and dull intelligence. Short stature is an additional feature of this autosomal dominant condition. A fourth family with Watson syndrome has since been reported. We have had the opportunity to review members of three of these four families. The clinical phenotype of Watson syndrome has been expanded to include relative macrocephaly and Lisch nodules in the majority of affected subjects, and neurofibromas in one-third of family members. Because the additional clinical findings enhance the similarity between Watson syndrome and neurofibromatosis 1, molecular linkage studies have been performed using probes flanking the NF1 gene on chromosome 17. Probe HHH202 showed the tightest linkage to Watson syndrome with a maximum lod score of 3.59 at phi = 0.0 (95% confidence limits of phi = 0.0-0.15). This suggests either that Watson syndrome and neurofibromatosis 1 are allelic, or that there is a series of contiguous genes for pulmonary stenosis, neurocutaneous anomalies, short stature, and mental retardation on 17q.     

Characteristics and perspectives of families waiting to adopt a child with Down syndrome.

PURPOSE: The study's purpose was to obtain information on the characteristics and perspectives of families interested in adopting children with Down syndrome. METHODS: A questionnaire-based survey was administered to individuals and families on a waiting list to adopt children with Down syndrome. Information on (1) demographic, (2) family structure, (3) Down syndrome exposure, (4) Down syndrome knowledge, (5) reasons for considering adoption, (6) adoption process, and (7) perspective on raising children with Down syndrome was assessed. RESULTS: From 199 mailed surveys, there were 72 respondents (36.2%) of whom six had previously adopted a child with Down syndrome. Forty-eight percent learned of the possibility of adopting children with Down syndrome through the Internet, whereas only one respondent obtained this information from a medical professional. The primary reasons for considering adoption were that prospective adoptive families were equipped with the necessary resources and had previous positive experiences with individuals who have Down syndrome. CONCLUSIONS: Many families are eager to adopt children with Down syndrome. Interest in this option stems from having resources to care for these children and previous positive experiences with individuals with Down syndrome. Information regarding adoption was rarely obtained from health care providers. When counseling pregnant women diagnosed with a Down syndrome fetus, adoption should be discussed so that all options regarding pregnancy management may be explored.     

MRX93 syndrome (BRWD3 gene): five new patients with novel mutations

Overgrowth syndromes (OGS) comprise a heterogeneous group of disorders whose main characteristic is that either the weight, height, or head circumference are above the 97th centile or 2 to 3 SD above the mean for age and sex. Additional features, such as facial dysmorphism, developmental delay or intellectual disability (ID), congenital anomalies, neurological problems and an increased risk of neoplasia are usually associated with OGS. Genetic analysis in patients with overlapping clinical features is essential, to distinguish between two or more similar conditions, and to provide appropriate genetic counseling and recommendations for follow up. In the present paper, we report five new patients (from four unrelated families) with an X-linked mental retardation syndrome with overgrowth (XMR93 syndrome), also known as XLID-BRWD3-related syndrome. The main features of these patients include ID, macrocephaly and dysmorphic facial features. XMR93 syndrome is a recently described disorder caused by mutations in the Bromodomain and WD-repeat domain-containing protein 3 (BRWD3) gene. This article underscores the importance of genetic screening by exome sequencing for patients with OGS and ID with unclear clinical diagnosis, and expands the number of reported individuals with XMR93 syndrome, highlighting the clinical features of this unusual disease.     

Refining the Primrose syndrome phenotype: A study of five patients with ZBTB20 de novo variants and a review of the literature

Primrose syndrome is a rare autosomal dominant condition caused by heterozygous missense variants within ZBTB20. Through an exome sequencing approach (as part of the Deciphering Developmental Disorders [DDD] study) we have identified five unrelated individuals with previously unreported, de novo ZBTB20 pathogenic missense variants. All five missense variants targeted the C2H2 zinc finger domains. This genotype‐up approach has allowed further refinement of the Primrose syndrome phenotype. Major characteristics (>90% individuals) include an intellectual disability (most frequently in the moderate range), a recognizable facial appearance and brain MRI abnormalities, particularly abnormalities of the corpus callosum. Other frequent clinical associations (in 50–90% individuals) include sensorineural hearing loss (83%), hypotonia (78%), cryptorchidism in males (75%), macrocephaly (72%), behavioral issues (56%), and dysplastic/hypoplastic nails (57%). Based upon these clinical data we discuss our current management of patients with Primrose syndrome.