Essam A.R. Ismail

Congenital Insensitivity to Pain with Anhidrosis: Novel Mutations in the TRKA (NTRK1) Gene Encoding A High-Affinity Receptor for Nerve Growth Factor

Congenital insensitivity to pain with anhidrosis (CIPA) is characterized by recurrent episodes of unexplained fever, anhidrosis (inability to sweat), absence of reaction to noxious stimuli, self-mutilating behavior, and mental retardation. Human TRKA encodes a high-affinity tyrosine kinase receptor for nerve growth factor (NGF), a member of the neurotrophin family that induces neurite outgrowth and promotes survival of embryonic sensory and sympathetic neurons. We have recently demonstrated that TRKA is responsible for CIPA by identifying three mutations in a region encoding the intracellular tyrosine kinase domain of TRKA in one Ecuadorian and three Japanese families. We have developed a comprehensive strategy to screen for TRKA mutations, on the basis of the genes structure and organization. Here we report 11 novel mutations, in seven affected families. These are six missense mutations, two frameshift mutations, one nonsense mutation, and two splice-site mutations. Mendelian inheritance of the mutations is confirmed in six families for which parent samples are available. Two mutations are linked, on the same chromosome, to Arg85Ser and to His598Tyr;Gly607Val, hence, they probably represent double and triple mutations. The mutations are distributed in an extracellular domain, involved in NGF binding, as well as the intracellular signal-transduction domain. These data suggest that TRKA defects cause CIPA in various ethnic groups.

CONGENITAL INSENSITIVITY TO PAIN WITH ANHIDROSIS : LACK OF ECCRINE SWEAT GLAND INNERVATION CONFIRMED

References 1. Cooper BA, Rosenblatt DS: Inherited defects of vitamin B12 metabolism. Ann Rev Nutr 1987;7:291-320. 2. Grasbeck R, Gordin R, Kantero I, Kuhlbäck B: Selective vitamin B12 malabsorption and proteinuria in young people. A syndrome. Acta Med Scand 1960;167:289-296. 3. Imerslund O: Idiopathic chronic megaloblastic anemia in children. Acta Paediatr Suppl 1960;119:1-115. 4. Tuchman M, Kelly P, Watkins D, Rosenblatt DS: Vitamin B12 responsive megaloblastic anemia, homocystinuria, and transient methylmalonic aciduria in cblE disease. J Pediatr 1988;113: 1052-1056.

Neonatal suppurative parotitis over the last 4 decades: report of three new cases and review.

Neonatal suppurative parotitis is a rare disease. Only 32 cases were reported in the English‐language literature between 1970 and 2004.

An Epidemiologic, Clinical, and Therapeutic Study of Childhood Guillain-Barré Syndrome in Kuwait: Is It Related to the Oral Polio Vaccine?

We studied Guillain-Barré syndrome, affecting children 12 years old or less, throughout Kuwait, in the period between January 1, 1992, and March 31, 1997. Nineteen children had the diagnostic criteria of Guillain-Barré syndrome, with an overall annual incidence rate of 0.95/100,000 population at risk. Female patients outnumbered male patients with a sex ratio of 1.4:1. There was a clustering of cases in winter and spring and in the year 1996. The disease symptoms were relatively severe in our patients because only 16% (3 of 19) of them were able to walk at the height of their illness, whereas the rest were bed or chair bound or needed assisted ventilation. Two patients had the electrodiagnostic features of axonal neuropathy and both had residual deficits on follow-up, whereas the rest recovered fully. All the patients received intravenous immunoglobulin. The mean time to walk unaided was 23.5 days (range, 2-84 days) after intravenous immunoglobulin and excluding the two patients with axonal neuropathy, and full recovery was achieved in a mean time of 103 days (range, 30-300 days). Contrary to previous studies, we found no correlation between oral polio vaccine administration and Guillain-Barré syndrome in 2 successive years (1995 and 1996) during a nationwide campaign targeting children less than 5 years old. (J Child Neut-ol 1998; 13:488-492).

Congenital Chloride Diarrhoea in Kuwait: A Clinical Reappraisal

Congenital chloride diarrhoea (CCD) is a recessively inherited disorder of chloride transport in the distal ileum and colon. Congenital chloride diarrhoea is a common metabolic disorder in Kuwait with an incidence of 1/3200. Clinical findings in 14 children with CCD are reported over a period of 4 years. Maternal polyhydramnios, abdominal distension, watery diarrhoea, and a high faecal chloride level > 90 mmol/l were the cardinal features in the neonatal period. In spite of the classical features of this disease 75 per cent of our cases were diagnosed beyond the neonatal period and all demonstrated chronic diarrhoea and failure to thrive, with hypochloraemia, hypokalaemia, and metabolic alkalosis. The practice of ultrasonic examination for pregnant women with polyhydramnios and, particularly, for those with previously affected siblings led to early identification of new cases among our population recently. The antenatal ultrasonic examination showed dilated intestinal loops which suggest CCD. The diagnosis was confirmed by a high faecal chloride level.

Allgrove syndrome with features of familial dysautonomia: A novel mutation in the AAAS gene

Allgrove syndrome (or triple‐A syndrome) is a rare autosomal recessive disorder characterized by alacrima, achalasia, adrenal insufficiency (glucocorticoid in the majority of cases) and autonomic/neurological abnormalities. This disease is now known to be caused by mutation in the AAAS gene located on chromosome 12q13. Diagnosis should be readily available when the full‐blown features are there, but it becomes less apparent when presentation is atypical or in the evolving process. We present a brother and sister (12 and 19 y old, respectively) born to consanguineous parents of Palestinian origin with Allgrove syndrome. The index patient was erroneously diagnosed to be a case of familial dysautonomia before the diagnosis of adrenal insufficiency was made at the age of 7.5 y, while his elder sister had only alacrima from birth and developed achalasia at the age of 15 y. She started to develop early evidence of adrenal disease at the age of 19 y. Both of them had neuroautonomic dysfunction. The diagnosis of Allgrove syndrome was confirmed in these two patients by studying the gene mutation in the family. The sequencing of the AAAS gene in the two patients identified a novel homozygous mutation within intron 5 (IVS5+1(G)→A). Both parents as well as all three other children were heterozygous for the same mutation.

Persistent hyperinsulinaemic hypoglycaemia of infancy (nesidioblastosis): a report from Kuwait.

We report nine Bedouin children from Kuwait with persistent hyperinsulinaemic hypoglycaemia (PHHI) seen over a 13-year period in two regional hospitals. The incidence of PHHI in this inbred community is high (1:20,000); five of them came from two families. All the children presented with seizures associated with severe and recurrent hypoglycaemia, eight presenting in the neonatal period and one at the age of 2 months. One child died soon after birth. All the others received diazoxide initially, which achieved remission in one while two siblings remain dependent on the drug. Long-acting somatostatin analogue (octreotide) was successfully used in one child. Four children underwent pancreatectomy, two showed diffuse and two had localized nesidioblastosis. Two children achieved normal neurodevelopmental milestones, four suffered mental retardation of varying degrees and three died. Early diagnosis and prompt treatment are essential to avoid the neurological damage associated with hypoglycaemia. In some cases, this condition is due to an autosomal recessive pattern of inheritance and it is therefore important to offer genetic counselling to families with one or more affected siblings.

Congenital absence of the infrahepatic segment of the inferior vena cava with deep venous thrombosis in an 8.5-year-old boy

In a recent study, the prevalence of interruption or congenital stenosis of the inferior vena cava (IVC) was found to be 0.15%. Embryological formation of IVC occurs between the fourth and eighth weeks of gestation; this period coincides with the development of most organs (spleen, liver, heart, and lungs). Thus, it is not surprising to have asplenia, polysplenia, situs inversus, congenital heart disease, lung and kidney malformation associated with IVC anomalies. The IVC is formed of four segments (in a caudal direction: hepatic, suprarenal, renal and infrarenal). These segments are formed by complex embryological processes involving the formation, fusion and regression of three main paired primitive veins called cardinal veins. Failure of proper development of one or all of these events leads to several congenital anomalies; one of these is the congenital absence of IVC (AIVC). It may be the entire IVC or one of its segments. It is also suggested that absence of the infrarenal segment of the IVC is not embryonic in origin, rather the result of intrauterine or perinatal thrombosis. The prevalence of AIVC in deep venous thrombosis (DVT) is about 5%. Approximately 90% of previously reported cases involved the absence of the suprarenal segment and 6% involved the renal or infrarenal segment. The combined absence of the suprarenal and infrarenal segments (infrahepatic) is so rare that only 10 cases were reported in the English-language literature prior to 2002. We present a patient who developed right iliofemoral thrombosis at the age of 8.5 years and was found to have this rare infrahepatic AIVC on computed tomography (CT) of the abdomen and magnetic resonance venography. There was no recurrence 16 months after discontinuing the anticoagulant treatment. To the best of our knowledge, this patient is one of the youngest patients reported to develop unprovoked DVT in association with infrahepatic AIVC. Case report

Chronic infantile neurological cutaneous articular syndrome in an Arab patient

neurological, cutaneous and articular (CINCA) syndrome when Prieur et al. reviewed 30 cases.1 With increased awareness of the disease, a few more cases have been reported since then.2 This syndrome, which is also known in the USA as infantile onset multisystem inflammatory disease (IOMID) or neonatal onset multisystem inflammatory disease (NOMID),2 is characterized by the triad of: (i) chronic urticaria-like skin rash, commonly observed in the neonatal period; (ii) arthritis of variable severity; and (iii) neurological manifestations. Other clinical features include fever, lymphadenopathy, hepatosplenomegaly, deafness, eye involvement (such as papilloedema with or without optic atrophy, conjunctivitis, keratitis, uveitis or chorioretinitis), macrocephaly with frontal bossing and saddle-back nose, delayed closure of the anterior fontanelle, clubbing, short thick hands and feet with wrinkled palms and soles and failure to grow. Although there is no diagnostic test, laboratory investigations are characterized by raised acute phase reactants, polyclonal hypergammaglobulinemia, increased cerebrospinal fluid cells and/or protein, in addition to bony radiological changes in those with severe arthropathy.1 It appears that this syndrome affects patients of different ethnic backgrounds and geographical locale.1,3–5 This is the first reported Arab patient and he had some unusual immunological data.

Transient hypocalcemia with elevated serum parathormone in an infant of a hyperparathyroid mother

Abstract An infant presented at the age of 80 days with a hypocalcemic fit. The mother was found to have asymptomatic parathyroid adenoma. The infants intact parathyroid hormone was high in the absence of Hypomagnesemia, renal failure or overt rickets, which are known causes of secondary end‐organ refractoriness. The patient was treated with calcium and 1‐alpha‐hydroxyvitamin D for only 2 weeks, but has remained asymptomatic and normocalcemic on follow‐up to the age of 2 years. It is believed that this has not been previously described and it is speculated that end‐organ refractoriness, though brief, can account for all the symptoms.