Dysmorphology and mental retardation: molecular cytogenetic studies in dysmorphic mentally retarded patients.

In an institutionalised population of 471 mentally retarded adult residents (436 males and 35 females), 18 patients (16 males and 2 females) with dysmorphic features were selected to perform FISH studies by using subtelomeric probes to discover cryptic terminal deletions or duplications, undetectable with standard banding techniques. In the 13 investigated patients, no abnormalities were found with a selected battery of subtelomeric probes. The results of cryptic chromosomal rearrangement studies are variable but the frequency of positive diagnostic findings seems to be lower than previously expected.

The clinical phenotype in institutionalised adult males with X-linked mental retardation (XLMR).

In an institutionalised population of 471 mentally retarded adult residents (436 males and 35 females), 22 males (i.e. 5 % of the male population) had XLMR, accounting for 36.1 % of the residents diagnosed with a monogenic disorder (n = 61). Fragile X syndrome (FRAXA) was diagnosed in 16 residents, X-linked mental retardation with marfanoid habitus (Lujan-Fryns syndrome) in 2, and non-specific X-linked mental retardation (MRX) in 4 males. The 4 MRX-patients included 3 male sibs of a family, carrying a mutation in the IL-1 receptor accessory protein-like gene, and one male patient member of the MRX-44 family (linkage with LOD-score of 2.90). In the group of 215 males with idiopathic mental retardation (MR), family histories and pedigree data were compatible with XLMR in 35 males (35/215 = 16.3 %) from 32 families. Of these 35 males, 5.7 % were microcephalic with dysmorphic features and 5.7 % macrocephalic; micro-orchidism and macro-orchidism were each found in 11.4 %. One macrocephalic male had also macro-orchidism and dysmorphic features. In this study, the diagnosis of XLMR could thus be proposed in 57 males i.e. 13.1 % of the total male population. The clinical phenotype, behavioural problems and follow-up data in these different subgroups of XLMR are presented.

Metabolic studies in older mentally retarded patients: significance of metabolic testing and correlation with the clinical phenotype.

In 471 adult mentally retarded adult patients (mean age 46 years; 92.6% males) living in an institution for the mentally retarded, a clinical examination, cytogenetic and molecular studies were done. 306 patients were screened for metabolic disorders. In 7 additional patients a metabolic disorder (phenylketonuria (n = 5), mucopolysaccharidosis type III (Sanfilippo syndrome, type A) (n = 1) and mucopolysaccharidosis type VII (Sly syndrome) (n = 1)) was diagnosed in the past. The abnormal metabolic findings in this group of 313 patients were classified in three categories and the clinical findings are reported: 1. metabolic disorders as the cause of mental retardation (MR), 2. metabolic disorders not explaining the MR, and 3. metabolic abnormalities of unknown significance. The first two groups included 16 patients, i.e. 26.2% of the group of monogenic disorders and 3.4% of the total population: phenylketonuria (PKU) (n = 5), S-sulfocysteinuria (n = 3), mucopolysaccharidosis type III (Sanfilippo syndrome, type A) (n = 1) and Gm1-gangliosidosis type 3 (n = 1) (first group), and mucopolysaccharidosis type VII (Sly syndrome) (n = 1), Niemann-Pick syndrome, type B (n = 1), cystinuria (n = 1) and hyperprolinemia type 1 (n = 3) (second group). The third group included patients with citrullinemia (n = 2), methionine sulphoxide reductase deficiency (n = 1), ornithinemia (n = 1), glycinuria (n = 20), neuraminaciduria (n = 8), uraciluria (n = 6) and diabetes mellitus (n = 2). Screening for Congenital Disorders of Glycosylation (CDG) in 144 patients and for Smith-Lemli-Opitz syndrome (SLO) in a selected group of 6 patients was normal. Of the total group of 306 patients screened for inborn errors of metabolism, only 5 (1.6%) were found with a true metabolic disorder. These 5 patients presented clinical symptoms, neurodegenerative or behavioural problems, indicating further metabolic screening. The present study illustrates that a selected group of patients with mental retardation of unknown origin are candidates for metabolic screening, especially if aberrant behaviour, neurodegenerative problems or dysmorphic features are present.

Cri du chat syndrome: changing phenotype in older patients.

The cri du chat syndrome or 5p deletion syndrome is a well-delineated clinical entity and has an incidence of 1/50,000 in newborn infants. A de novo deletion is present in 85% of the patients. Ten to 15% are familial cases with more than 90% due to a parental translocation and 5% due to an inversion of chromosome 5. Although the size of the deleted segment varies, the critical segment that is deleted in all patients appears to be 5p15.2. The clinical picture is well known in younger patients and includes the typical high-pitched cry, psychomotor retardation, microcephaly, growth rate failure, and craniofacial abnormalities including round face, hypertelorism, broad nasal bridge, downward slanting palpebral fissures, and micrognathia. With advancing age, the clinical picture becomes less striking. We present seven patients with 5p deletion syndrome, who were between age 16 and 47 years. Comparing their phenotype at several ages, a change of their phenotype was noted. Some of the clinical characteristics became more evident such as long face, macrostomia, and scoliosis. All patients were severely or profoundly mentally retarded except one patient who was mildly mentally retarded. The diagnosis was difficult to make in some of the patients who were first seen at an older age. In some of them, the craniofacial appearance resembled that seen in Angelman syndrome. Most patients had periods of destructive behavior, self mutilation, and aggression. The clinical diagnosis should be confirmed as soon as possible with cytogenetic investigation to provide specific support, prevention, and treatment of complications. Therefore, it is important to perform follow-up studies in young children to determine their outcome after infant-stimulation programs.

Angelman syndrome in three adult patients with atypical presentation and severe neurological complications.

Angelman syndrome (AS) is a distinct neurogenetic disorder and the phenotype is well known in childhood and adolescence. However, with advancing age the clinical and behavioral phenotype changes. In adulthood, the phenotype can be rather aspecific. We report on AS in 3 severely to profoundly mentally retarded patients, who developed severe neurologic complications of severe tremor, spasticity and coordination problems, resulting into severe loss of function. They presented atypical craniofacial features, short stature, epileptic seizures, microcephaly, brachytelephalangy and absent speech. Two patients presented at an older age a change in day-night rhythm. Based on this experience, we conclude that all severely to profoundly mentally retarded patients with atypical phenotype, spasticity, absent speech, epileptic seizures and changed day-night rhythm are candidates for further cytogenetic and molecular investigation for AS. Clinical photographs of the patient at a younger age can be helpful. The presence of the typical EEG pattern with frontal triphasic delta waves may direct to the diagnosis of AS.

Down syndrome in a population of elderly mentally retarded patients: genetic-diagnostic survey and implications for medical care.

Ninety-six adults with Down syndrome (DS) from an institutional setting of 591 mentally retarded were investigated systematically with respect to cytogenetic diagnosis, mental functioning and dementia, ophthalmological and audiological abnormalities, and thyroid function. Seventy of the 96 DS patients (73%) were older than 40 years. Only 4.2% were females. Trisomy 21 was found in 86% and mosaic trisomy 21 in 13%. Eighty-two percent of the patients were moderately or severely mentally retarded, 15% were profoundly retarded, and only 3% mildly retarded. Nineteen percent of the patients had dementia. This number increased to 42% of the patients above the age of 50 years. Epileptic seizures were present in 16.7% of all patients, and in 50% of the patients with dementia. Only 17% of the patients in the present study had normal visual acuity, one-third had at least moderately reduced vision. This number increased significantly with age: in the age group 50-59 years almost half of the patients had moderate to severe vision loss. Seventy percent of the patients had moderate, severe, or very severe hearing loss, which was undiagnosed before systematic hearing testing was performed. Increased (48%) or decreased (1%) TSH level was found in 49% of the patients examined for thyroid functions. We suggest a regular screening of all adults with DS to diagnose early dementia, epilepsy, hypothyroidism, and early loss of visual acuity and hearing, with special attention to the group of patients who are severely to profoundly mentally retarded and those with advanced age. Cytogenetic studies are necessary to confirm the clinical diagnosis and are essential for genetic counseling purposes.

Fountain syndrome: further delineation of the clinical syndrome and follow-up data.

We present five patients with the clinical diagnosis of Fountain's syndrome, an autosomal recessive entity with mental retardation, deafness, skeletal abnormalities and coarse face with full lips as cardinal features and review all cases reported so far. We report two new isolated cases, and present follow-up data on three previously reported patients. The clinical features of all these patients are presented to further delineate the clinical picture and the natural course of this rare syndrome. We propose that epilepsy, short stature, large head circumference, broad, plump hands and the remarkable behavior are important accessory findings of this syndrome. The clinical features of this syndrome become more evident with advancing age.

Renal agenesis and trisomy 22: case report and review.

Renal agenesis has been reported in the literature in a wide variety of chromosomal abnormalities. Trisomy 22 is frequently seen in first trimester miscarriages but is extremely rare in life-borns. The authors report on a second trimester female foetus with oligohydramnios sequence secondary to bilateral renal agenesis and trisomy 22 and review the literature.

Zimmermann-Laband syndrome in a patient with severe mental retardation.

Zimmermann-Laband syndrome in a patient with severe mental retardation: The Zimmermann-Laband syndrome (ZLS) is a rare autosomal dominant disorder characterized by gingival hyperplasia or fibromatosis, various skeletal anomalies including dysplasia of the distal phalanges of thumbs and halluces, vertebral defects, and hepatosplenomegaly. Thus far, 23 cases, including 11 patients from 2 families, have been reported. Most cases of ZLS have a normal intelligence although some cases are mildly retarded. Differential diagnosis includes other causes of gingival hyperplasia. We report on a patient with ZLS and severe mental retardation and review the literature. We conclude that severe mental retardation is a feature of the syndrome.

Down-Turner syndrome: case report and review.

We present a male patient with Down-Turner mosaicism (45,X/46,X,+21/47,XY,+21) and review 27 similar cases reported so far. Clinical features of Down's syndrome were present in all cases, whereas a combination of features of both Ullrich-Turner syndrome and Down's syndrome was reported in 61% of the patients. However, one has to bear in mind that several stigmata of Ullrich-Turner syndrome can also be present in patients with Down's syndrome and vice versa. In most of the patients two different cell lines were encountered, although cases with one, three, and even four different cell lines have been reported. Of 28 patients, 21 showed female external genitalia, four were phenotypically male, and three showed ambiguous genitalia. Only six patients (21%) carried a Y chromosome, which is far less than expected.