Virilization of the external genitalia and severe mental retardation in a girl with an unbalanced translocation 1;18.

A female infant with dysmorphic facial features, psychomotor retardation, and clitoris hypertrophy is described. Molecular cytogenetic analyses revealed a de novo unbalanced translocation, causing partial monosomy 1p36 and partial trisomy 18q22. Monosomy 1p was confirmed by FISH, and trisomy of the distal part of chromosome 18q was demonstrated by microFISH. Gene copy number changes in these chromosomal regions were determined by array-CGH. The absence of a number of facial dysmorphic signs, and the presence of clitoris hypertrophy indicate that the combination of a del(1p36->pter) with a dup(18q22->qter) may lead to a unique phenotypic constellation. The findings at birth and at age 12 years in our patient are compared with genotype-phenotype correlations discussed in the literature.

Familial association of intracranial aneurysms and multiple congenital anomalies.

The familial occurrence of intracranial aneurysms and the possible relationship with connective tissue disease are discussed. We studied a large family in which seven members presented with aneurysms. Another family member presented with a subarachnoidal hemorrhage. Two other family members each presented with Marfan's syndrome and an unclassified multiple congenital anomalies syndrome, respectively. The multiplicity of the aneurysms in four members is in excess of that found in sporadic or familial cases with intracranial aneurysms. We suggest a common cause, eg, a connective tissue disorder for both the intracranial aneurysms, the Marfan's syndrome, and the unclassified syndrome.

Further delineation of the 3-M syndrome with review of the literature.

The 3-M syndrome is a clinically recognizable disorder characterized by prenatal and postnatal growth retardation and a spectrum of consistent minor anomalies. Intelligence seems normal. Inheritance is probably autosomal recessive, with possible expression of the mutant gene in the heterozygote. Three sibs with the 3-M syndrome are reported, together with an extensive review of the pertinent literature.

Craniofacial dysostosis, hypertrichosis, genital hypoplasia, ocular, dental, and digital defects: confirmation of the Gorlin-Chaudhry-Moss syndrome.

We report clinical, orofacial and radiological manifestations in a 4-year-old girl and a 33-year-old female with the Gorlin-Chaudhry-Moss (GCM) syndrome. Typical findings in the GCM syndrome are short stature, stocky body build, midface hypoplasia, small eyes, downslanting palpebral fissures, conductive hearing loss, highly arched and narrow palate, malocclusion, abnormally shaped teeth, oligodontia, microdontia, low scalp hairline, hypertrichosis of scalp, face, trunk and limbs and genital hypoplasia. Radiological features include premature synostosis of the coronal suture, brachycephaly, and maxillary under-development. Hypoplasia of the distal phalanges of fingers and toes (also present in the 2 original cases) represents a further manifestation of the GCM syndrome.

The Dutch Uniform Multicenter Registration system for genetic disorders and malformation syndromes.

In medical genetics, several systems are used to classify and code genetic disorders for the purpose of automated registration. In the Netherlands, a genetic diagnosis code system has been developed that links a unique four-digit code to a principal description and all current synonyms. The main goal of this coding system is to enable nationwide uniformity of coding, without losing access to information stored in the past, identified by the ICD/BPA code (the International Classification of Diseases as adapted by the British Paediatric Association) and/or the MIM code (McKusick's classification in Mendelian Inheritance in Man). To this effect, the Dutch diagnosis code is cross-referenced with the 2 pre-existing classification systems. Developments in medical genetics make regular updates of all coding systems necessary. In the Netherlands, new diagnosis codes are assigned centrally to preserve uniformity and distributed periodically to all 8 clinical genetic centers. Diagnosis codes are assigned in numerical order of inclusion, enabling quick and easy updates. It is possible to include subclassifications of disorders according to pattern of inheritance, gene location, and gene mutations and to cover all disorders and disorder subtypes which are not clearly distinguished by the 2 pre-existing classification systems. The architecture of the coding system is suitable for international use. It offers a practical solution for clinical geneticists in need of a coding system suitable for clinical use. The use of the diagnosis code will also facilitate reliable comparison of data and nationwide genetic epidemiological studies.

Sutural cataract, retinitis pigmentosa, microcephaly and psychomotor retardation. A new autosomal recessive disorder?

We report four children (three sibs and one sporadic case) with congenital sutural cataract (opacity of the sutures of the crystalline lens), retinitis pigmentosa (leading to diminished visual acuity), microcephaly, and moderate to severe psychomotor retardation. The three sibs (two F and one M) were born to healthy, consanguineous Moroccan parents; the sporadic case is an 11-year-old Dutch girl who presented at the age of nine months with a small head circumference (third percentile) and sutural cataract. Psychomotor development was retarded in all cases, retinitis pigmentosa became evident during middle or late childhood. Congenital cataract has been described in association with a large number of various congenital abnormalities, such as renal, nervous system, skeletal, dermal and ocular (including retinal) defects. A computer-assisted literature search has not revealed similar cases to those presented here. The cases described here appear to have a previously undescribed combination of ophthalmological and cerebral abnormalities. The inheritance of the condition appears to be autosomal recessive as a brother and two sisters (offspring of normal consanguineous parents) are affected. The differential diagnosis is discussed.

Treatment of intact familial intracranial aneurysms: a decision-analytical approach.

Clinical decision analysis is applied to the treatment decisions for four patients with unruptured familial aneurysms. The surgical treatment was uneventful in all patients except one with mild mixed aphasia and facial weakness postoperatively; these deficits disappeared in less than 2 years. In the decision analysis, discounted Quality Adjusted Life Years are used as an outcome measure. Probability estimates are extracted from the literature when available. It is concluded that the decision to treat the aneurysm neurosurgically in three of the four patients was correct. In two of these three patients, the decision cannot be altered by plausible changes in estimated data. For the third patient, only the combination of a low probability of rupture, a high surgical mortality and morbidity, and high discount favors conservative treatment. In the fourth patient, a toss-up situation exists. More knowledge of the probability of rupture, the probability of the development of other aneurysms, and the results of operation on intact intracranial aneurysms would have made the analysis more accurate. Clinical research should address these issues.

Genetic heterogeneity of hereditary motor and sensory neuropathy type VI.

Charcot-Marie-Tooth disease comprises a heterogeneous group of neurologic disorders that shape peripheral motor and sensory neuropathy. A classification of these disorders was proposed in 1975, defining seven types of hereditary motor and sensory neuropathy. Clinical features of hereditary motor and sensory neuropathy type VI are muscle weakness and atrophy in leg and hand muscles, leading to progressive disability and loss of vision and progressing to blindness due to optic atrophy. Hereditary motor and sensory neuropathy type VI was first reported in 1879 by Vizioli, who described a kinship in which a father and two sons presented with peroneal muscular atrophy in association with optic atrophy. Since then, at least nine similar cases have been reported: three sporadic cases, two pairs of siblings who were offspring of consanguineous parents, and one pair of siblings who were offspring of unrelated parents suggesting autosomal recessive inheritance. Vertical transmission has been reported only by Vizioli. We present a father and two offspring (one boy and one girl) with the above-mentioned characteristic features of hereditary motor and sensory neuropathy type VI. Vizioli's kinship and either an autosomal recessive or autosomal dominant pattern of inheritance.

Megalencephaly: definition and classification.

The various definitions and classifications of megalencephaly are reviewed, and numerous diseases and syndromes associated with megalencephaly are listed. A new definition of megalencephaly based on quantitative radiographic features is proposed. We define megalencephaly as a brain volume which exceeds the mean by more than twice the standard deviation. Furthermore, a modified etiopathogenic classification of megalencephaly results in three main groups, viz anatomic, metabolic and dynamic megalencephaly. The clinical pictures in these main groups of megalencephaly, and the largest subgroup of anatomic megalencephaly, familial anatomic megalencephaly, appear to be quite different.

MCA/MR syndrome in two female siblings: new entity or variant examples of Coffin-Lowry versus Atkin-Flaitz syndromes?

We report two sisters with mental retardation, coarse facial features, telecanthus, flat malar region, prominent lower lip, kyphoscoliosis, and tapering fingers. Although these patients' phenotypes showed considerable overlap with the Coffin-Lowry and the Atkin-Flaitz syndromes, their overall picture makes these diagnoses controversial.

Interstitial deletion 11q. Case report and review of the literature.

A mildly retarded male with a unique interstitial deletion 11 (pter-->q22.3::q23.2-->qter) is described. To the best of our knowledge this patient is the first case with this specific type of deletion. The clinical features and cytogenetic findings of this patient are compared with those of previously reported cases with interstitial deletions 11q and patients with terminal deletions involving band 11q24.1 (leading to the so-called Jacobsen syndrome).

Follow-up of a patient with partial trisomy 9p and partial monosomy 8p; description of physical and psychosocial development.

A patient is described with partial trisomy 9p and partial monosomy 8p due to a maternal translocation (t(8;9)(p23;p13)). The clinical phenotype is compatible with the partial trisomy 9p syndrome. This is a clinically recognizable syndrome with mental retardation as a constant feature. Little is known about the outcome and level of functioning of patients with this condition. We present the follow-up of a patient with partial trisomy 9p who has been regularly examined from birth until age 10 years.

[Prognosis in the cri-du-chat syndrome]. / De prognose van het cri-du-chat syndroom.

Cri-du-chat syndrome (5p-) is one of the most frequently occurring chromosomal deletion syndromes in man. Clinical findings have been described extensively in literature, but documentation of the patients' mental development has been poor. Recently the clinical heterogeneity and variance in psychomotor development was studied in a large series of patients. Review of the literature revealed that some 15% of the cases were found to be familial, there appears to be a slight correlation between karyotype and phenotype and the positive effects of early stimulation programs on the patients' prognosis is pointed out. Some 60% of the patients need regular medical care and nearly all are mentally retarded. However a wide spectrum of developmental abilities is displayed and a number of patients can be reared at home for several years. Life expectancy depends on the number and severity of birth defects.

Pure gonadal dysgenesis in a triple-x female.

A tall 15 1/2-year-old-girl with an xxx sex chromosome complement, absence of secondary sexual characteristics and histologically verified pure gonadal dysgenesis is described. In contrast to patients with an xxy sex chromosome configuration who--after puberty--are recognisable by typical somatic abnormalities, triple-x females generally show no physical anomalies. Speech and language problems can be features of the triple-x condition; ovarian dysfunction in triple-x females has been described only sporadically. Probably one patient is the second case described having this chromosomal aberration combined with pure gonadal dysgenesis. The presence of three x chromosomes (and thereby possibly extra growth determinants) could be the reason for the extra growth potential in these patients. This contrasts with the reduced growth in patients with the xo sex chromosome configuration who tend to remain small.

Interstitial deletion in 3q in a patient with blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) and microcephaly, mild mental retardation and growth delay: clinical report and review of the literature.

We present a boy with blepharophimosis, ptosis, epicanthus inversus, microcephaly, mild mental retardation, and growth delay. Chromosomal analysis revealed a male karyotype with an interstitial deletion in the long arm of chromosome 3. DNA-analysis showed that the deletion is of maternal origin and encompasses the region between markers D3S1535 and D3S1593. The deletion contains not only the FOXL2 gene, but also the gene encoding ataxia-telangiectasia and Rad3-related protein (ATR). Mutations in FOXL2 have been shown to cause blepharophimosis-ptosis-epicanthus inversus syndrome (BPES). ATR has been identified as a candidate gene for Seckel syndrome, an autosomal recessive syndrome that comprises growth retardation, microcephaly, and mental retardation. We hypothesize that our patient has a contiguous gene syndrome and that the non-BPES-associated abnormalities (microcephaly, mild mental retardation, and growth delay) are the result of the deletion of the maternal ATR gene. However, it has not yet been excluded that haploinsufficiency of some other gene in this region plays a role.

Familial occurrence of intracranial aneurysms in childhood: a case report and review of the literature.

This report describes three individuals belonging to one family, who were affected with ruptured intracranial aneurysms (IAs) at a rather young age, 4, 15 and 23 years respectively. Familial IAs at this young age have not been described before. The evidence for a developmental, eventually inherited origin of familial IA in childhood is discussed with reference to the low occurrence of non-familial IA in childhood, IA-features in non-familial cases (localisation, multiplicity, size) and the association with (other) congenital malformations in the 0-5 years group.

Interstitial deletion of the long arm of chromosome 11.

A girl with an interstitial deletion of the long arm of chromosome 11 is described. The patient was mildly mentally retarded and showed some facial dysmorphic features, including hypertelorism, ptosis, and cleft palate.