[Allgrove syndrome (triple A). Finding of a mutation not described in the AAAS gene]. / Síndrome de Allgrove (triple A). Hallazgo de una mutación no descrita en el gen AAAS.

Allgrove syndrome (triple A) is a rare autosomal recessive disease. The classic triad includes, congenital adrenal insufficiency due to ACTH resistance, achalasia of the cardia and alacrimia. Neurological abnormalities are associated with autonomic neuropathy, sensory and motor defects, deafness, mental retardation, Parkinsonism and dementia. The gene responsible is the ADRACALIN or AAAS encoding a protein called ALADIN. We report a case of a 19 year-old male, assessed when he was 10 years old in our department due to suspected storage disease. Mild mental and language retardation, hypernasal voice, sensory-motor neuropathy with autonomic involvement and signs of spastic paraparesis, alacrimia. gastroesophageal reflux, and achalasia. Molecular studies showed to mutations, the undescribed p.Tyr 19 Cys, and IVS14 +1 G.

First experience of enzyme replacement therapy with idursulfase in Spanish patients with Hunter syndrome under 5 years of age: case observations from the Hunter Outcome Survey (HOS).

Hunter syndrome (mucopolysaccharidosis type II [MPS II], OMIM309900) is a rare X-linked lysosomal storage disorder caused by deficiency of the enzyme iduronate-2-sulphatase, resulting in accumulation of glycosaminoglycans (GAGs), multisystem organ failure and early death. Enzyme replacement therapy (ERT) with idursulfase is commercially available since 2007. Early access programs were established since 2005. However, limited information on the effects of ERT in young children is available to date. The aim of this analysis was therefore to determine the effects of ERT on patients younger than 5 years of age. We report data from six Spanish patients with confirmed Hunter syndrome who were younger than 5 years at the start of ERT, and had been treated with weekly intravenous infusions of idursulfase between 6 and 14 months. Baseline and treatment data were obtained from the Hunter Outcome Survey (HOS). HOS is an international database of MPS II patients on ERT or candidates to be treated, that collects data in a registry manner. HOS is supported by Shire Human Genetic Therapies, Inc. (Cambridge, MA, USA). At baseline, all patients showed neurological abnormalities, including ventriculomegaly, hydrocephaly, cerebral atrophy, perivascular changes and white matter lesions. Other signs and symptoms included thoracic deformity, otitis media, joint stiffness and hepatosplenomegaly, demonstrating that children under 5 years old can also be severely affected. ERT reduced urinary GAG levels, and reduced spleen (n = 2) and liver size (n = 1) after only 8 months. Height growth was maintained within the normal range during ERT. Joint mobility either stabilized or improved during ERT. In conclusion, this case series confirms the early onset of signs and symptoms of Hunter syndrome and provides the first evidence of ERT beneficial effects in patients less than 5 years of age. Similar efficacy and safety profiles to those seen in older children can be suggested, although further studies including a direct comparison with older patients would still be required.

[Digestive malformations and their associations to syndrome condition and genetic defects]. / Malformaciones digestivas y su asociación a patología sindrómica y defectos genéticos.

INTRODUCTION: The incidence of disease syndromes and genetic defects in patients with malformations is much higher than in the general population. We reviewed our experience in infants with gastrointestinal malformations to know the incidence of genetic defects and syndromic presentation, for purposes of carrying out the most complete assessment and treatment. MATERIAL AND METHODS: We recruited 161 patients with one or more malformations or congenital gastrointestinal pathology. We evaluated: type of malformation (isolated or syndromic), association with polimalformative complex, genetic testing and its results. RESULTS: The main diagnosis, from highest to lowest incidence, is intestinal malrotation (17.18%), Hirschsprung's disease (13.64%), Meckel's diverticulum (13.14%), oesophageal atresia (12.13%), anorectal malformation (11.12%), diaphragmatic hernia (6.57%), duodenal atresia (5.56%), small bowel atresia (4.55%), omphalocele (4.04), and other (12.07%). In 45.3% the malformation is not isolated. 27.4% appear as syndrome, 4.1% as development defect and 2.7% as association. Genetic study was performed in 30.43%, detecting defects in 36.7% of the studies. Down syndrome (n = 8) is the most frequent. DISCUSSION AND CONCLUSIONS: Our experience with these patients is similar to that provided in the literature. We consider that it is important to identify any associated anomalies, especially heart disease, craniofacial anomalies and other gastrointestinal malformations, because they condition the patient's management. Pathologies that are often associated with other defects require more effort for their detection. The knowledge of these patients is essential for correct treatment.

[Esophageal atresia in the Goldenhar syndrome]. / Atresia de esófago en el síndrome de Goldenhar.

Among the multiple congenital defects associated to esophagueal atresia, the characteristic ones of the Goldenhar syndrome usually are not included. The high incidence has been reported, about 5% of esophagueal atresia in patients with Goldenhar syndrome. Our experience includes two patients with this association who presented anesthetic problems and surgical complications associated with gastroesophageal reflux and esophageal anastomosis.

First report of a patient with a mixoploidy 47,XXX/94,XXXXXX.

We present a 16 years old female with a chromosomal mixoploidy and multiple phenotypic anomalies. Peripheral blood G-band karyotype was 47,XXX and her skin fibroblast karyotype revealed a mosaic with a 47,XXX cell line in 88% of metaphases and a 94,XXXXXX cell line in 12% of metaphases, consistent with a hypertetraploidy. The most prominent clinical signs were: short stature, left upper limb asymmetry, senile-like appearance, generalized hypertrichosis, and small hands and feet. Radiological examination showed bone dysplasia. The result of molecular studies demonstrated that the patient inherited the two X chromosomes from the mother and one from the father, indicating that her 47,XXX trisomy resulted from an oogenesis error in the first meiotic division. The 94,XXXXXX cell line was likely the result of a cytokinesis error. To our knowledge, this is the first documented patient with a trisomy and a hypertetraploidy.

[Familial adenomatous polyposis: Gardner's syndrome]. / Poliposis adenomatosa familiar: síndrome de Gardner.

Familial adenomatous polyposis (PAF) associated to soft tissue tumors or osteomas constitutes the Gardner's syndrome of autosomal dominant inheritance. The risk of colorectal cancer in these patients is 100%. We present a patient with Gardner's syndrome who was had colectomy at early age. An eleven years old boy he was evaluated due to a family history of PAF and subcutaneous tumors (occipital and left thigh). Genetic profile shows a mutation in gene APC and the colonoscopy confirms the polyposis; the biopsy also suggested moderate dysplasia. When the patient reached the age of twelve, a total colectomy with colorectal mucosectomy was performed. Cystic subcutaneous lesions (epidermoid cysts) were also excised. In the postoperative period there were no complications. The prophylactic colectomy, is the only effective treatment to prevent the colorectal cancer. Gardner's syndrome patients requires periodic controls to rule out the appearance of new tumors or anomalies in the retine. The duodenoscopy is essential in the follow up of these patients because of the frequency of duodenal affectation.

[De novo partial duplication of the distal segment of the long arm of chromosome 5 (q31--> qter). Report of a new case]. / Duplicación parcial de novo del segmento distal del brazo largo del cromosoma 5 (q31 --> qter).

We report a case of de novo partial duplication of the distal segment of the long arm of chromosome 5 (q31--> qter). The patient showed dysmorphic features (flat face, short and horizontal palpebral fissures, depressed and broad nasal bridge, wide nose with hypoplastic alae nasae, short and flat philtrum, high arched palate, micrognathia, anomalies of the ears), redundant adipose panniculus of the neck, proximal shortening of the limbs, flexion contractures, long and distally widened fingers, bilateral clubfoot, single umbilical artery, hypoplasia of lung and pulmonary arteries, atrial septal defect and patent ductus arteriosus. She died 23 hours after birth from respiratory failure. Chromosome analysis with high resolution GTG bands showed 46,XX,1p1, which was interpreted as a partial duplication of the distal long arm of chromosome 5 (q31--> qter). Fluorescence in situ hybridization analyses with whole chromosome painting technique for chromosome 5 proved that this extra region belonged to chromosome 5. Our case is the first to have a de novo partial duplication of this chromosome segment.

[Partial trisomy 18q due to maternal reciprocal translocation 4;18]. / Trisomía 18q parcial derivada de translocación recíproca 4;18 materna.

We report a new case of partial trisomy 18q due to a balanced reciprocal translocation 4;18 in the mother. The female infant had a partial trisomy of the long arm of chromosome 18 associated with a partial monosomy of distal 4q. The infant showed many of the main clinical features of trisomy 18, such as dysmorphic face, congenital heart defect, crossing of the second and fifth fingers over the third and fourth with flexion contractures, and abnormal genitalia. We believe that the trisomy 18 phenotype requires a large region of 18q and that the greater the trisomic fragment, the more severe the expression. We stress the importance of genetic counseling to carriers of balanced translocations. The risk for each case should be evaluated and information should be given on the possibility of prenatal diagnosis.

[Epidemiological aspects of children of women with bicornuate uterus]. / Aspectos epidemiológicos de los hijos de mujeres con útero bicorne.

BACKGROUND: Most published papers on women with a bicornuate uterus analyze their fertility problems, as well as certain pregnancy complications. We have not found any epidemiological study on the infants of mothers with this uterine malformation. Only in some papers a reference is made about the relationship of maternal bicornuate uterus with congenital deformations and disruptions in their infants. PATIENTS AND METHODS: Using data from the Spanish Collaborative Study of Congenital Malformations (ECEMC), which has a case-control methodology, some characteristics in a series of 26,945 malformed infants, such as birth weight, sex, gestational age, umbilical cord length, placental weight and maternal age, were analyzed by separating infants of mothers with normal uterus and those of mothers with a bicornuate uterus. RESULTS: Results showed that women with a bicornuate uterus have more daughters than sons and an increased risk for intrauterine growth retardation and prematurity with respect to infants of mothers with a normal uterus. On the other hand, the risk of having an infant with congenital defects is higher for women with a bicornuate uterus than for those with a normal uterus. CONCLUSIONS: Pregnancies of women with a bicornuate uterus have to be considered at risk since they have more risk for complications and for having an infant with congenital defects, premature birth and with intrauterine growth retardation.

Kabuki make-up (Niikawa-Kuroki) syndrome in five Spanish children.

We describe 5 Spanish children with Kabuki make-up syndrome (KMS)-3 females and 2 males-identified in Badajoz, Spain, between 1988 and 1990. All had the characteristic clinical and radiological manifestations of the syndrome. Psychomotor/mental retardation, postnatal growth deficiency, distinctive facial appearance, sagittal vertebral clefts, and dermatoglyphic abnormalities were present in all 5. Congenital heart defects were present in 4 patients. In addition, one had myopia, astigmatism, and bilateral paralysis of the VI cranial nerve. Another had apparent fusion of the hamate and capitate. An additional patient, as well as his mother, had an apparently balanced 15/17 translocation [46,XY,t(15;17) (15q;21q)]. The fact that these patients were ascertained in a catchment area of approximately 250,000 inhabitants and in a relatively limited period of time suggests that the prevalence of the KMS may be higher than previously recognized.

Tracheoesophageal anomalies in oculoauriculovertebral (Goldenhar) spectrum.

Tracheoesophageal fistula, with or without esophageal atresia (TEF/EA) appears to be a defect of blastogenesis, as is the oculoauriculovertebral (Goldenhar) spectrum (OAVS), with which it has occasionally been associated. We reviewed the records of all OAVS patients evaluated through the University of South Florida Regional Genetics Program between 1985 and 1993. Of 60 OAVS patients, three had TEF/EA. These results suggest that TEF/EA in association with OAVS is underreported. The occurrence of TEF/EA should prompt a thorough search for other known anomalies of OAVS.

Clitoromegaly in neurofibromatosis.

Genitourinary neurofibromas are rare and clitoral involvement in neurofibromatosis (NF) has been reported infrequently. However, when it occurs, clitoromegaly is often the presenting sign. In many cases, it is congenital. In 236 families with type 1 neurofibromatosis (NF-1) evaluated through the USF Regional Genetics Program between January 1982 and September 1993, four patients had clitoral involvement. In three, involvement was limited to the clitoris. Biopsy/surgical excision in two of them showed a neurofibroma in one and non-specific hamartomatous soft tissue overgrowth in the other. In the fourth patient, the involvement was asymmetric and extended to the labia majora and mons pubis. Endocrine studies and chromosomes in all patients were normal; there was no exposure to androgens, progestins, or coumadin. There was no gestational history of maternal luteomas. Review of the literature documented 26 patients with NF and clitoral involvement. Clitoral involvement in NF-1 appears to be more common than previously reported and the differential diagnosis of ambiguous genitalia should include clitoromegaly due to NF. Pathogenesis of clitoral lesions appears similar to other lesions of NF. Biopsy of such lesions appears to be justified only when malignancy is suspected.