A 6-year-old boy, of consanguinous parents, presented with severe rickets and alopecia; he was found to have hypocalcaemia and elevated circulating 1,25-dihydroxyvitamin D [1,25-(OH)2D] levels. He showed no calcaemic response to 1,25-(OH)2D3 or ergocalciferol given for 3 or more months in daily doses as high as 48 micrograms and 6 X 10(6) IU, respectively. Analyses with cultured skin fibroblasts revealed a normal capacity and affinity for 1,25-(OH)2D3 in soluble extracts ('cytosol') and in nuclei of intact cells but no detectable response of 25-(OH)D3 24-hydroxylase to 1,25-(OH)2D3 in high concentration. Treatment with high doses of calcium (3-4 g elemental calcium orally per day) produced a striking clinical and radiological improvement. We conclude that high oral doses of calcium can replace many of the actions of calciferols. Therapy with high doses of calcium should be tried in similarly affected cases that appear totally or partially unresponsive to calciferols.
To describe the clinical, ophthalmological, endocrinological and radiological features of 10 Saudi children with the syndrome of septo-optic dysplasia and hypothalamic hypopituitarism.All patients underwent complete ophthalmological and endocrinological evaluation at the Pediatric Endocrine Clinics, King Faisal Specialist Hospital and Research Center and King Fahad National Guard Hospital, Riyadh, Kingdom of Saudi Arabia, from October 1999 through to May 2004. The hormonal evaluation included growth hormone, adrenocorticotrophic hormone, thyroid stimulating hormone, gonadotropin and anti diuretic hormone testing, and the neuroradiological assessment included brain magnetic resonance imaging or computed tomogram scanning, or both.The current age of patients ranged from 18- months to 5-years. The mean age of initial presentation for endocrine evaluation was 14-months. Hormonal studies indicated that all children had multiple pituitary hormone deficiencies (2 or more of the pituitary hormones were deficient). Ten children had growth hormone deficiency, 8 had thyroid stimulating hormone deficiency, 8 had adrenocorticotrophic hormone deficiency, 2 children were suspected to have gonadotropin deficiency and central diabetes insipidus was present in one patient. Pendular nystagmus and impaired vision were common initial signs. All children had bilateral optic nerve hypoplasia. Neuroradiologic findings were variable. Eight children had absent septum pellucidum, 3 had pituitary gland hypoplasia, 2 had pituitary stalk dysplasia (pituitary stalk was either attenuated or not visualized), 2 had absent corpus callosum and one had absent posterior pituitary high intensity signal. All patients were replaced with appropriate hormonal replacement therapy. Two male children had micropenis which responded to testosterone therapy.The syndrome of septo-optic dysplasia is commonly associated with hypothalamic hypopituitarism including anterior and posterior pituitary hormonal deficiencies. Early diagnosis of this syndrome is critical as the hormonal deficiencies can be life threatening.
The association of microtia, midface hypoplasia, micrognathia, lower limb arthrogryposis, absent patella, and cryptorchidism was first described by Meier et al. [1959]. Gorlin et al. [1975] reported remarkably similar findings in a male patient associated with short stature. Boles et al. [1994], reporting on two sisters and reviewing six previously described patients, suggested the eponym Meier-Gorlin syndrome (MGS), which includes the triad of pre- and postnatal growth retardation, bilateral microtia, and patellar aplasia/hypoplasia. Ear-patella-short stature syndrome (MGS) has become one of the increasingly recognized disorders and to date, at least cases of 35 patients have been published [Meier et al., 1959; Gorlin et al., 1975; Hurst et al., 1988; Cohen et al., 1991; Boles et al., 1994; Lacombe et al., 1994; Buebel et al., 1996; Teebi and Gorlin, 1997; Fryns, 1998; Loeys et al., 1999; Verhallen et al., 1999; Terhal et al., 2000; Bongers et al., 2001; Cohen et al., 2002; Feingold, 2002; Shalev and Hall, 2003; Dudkiewicz and Tanzer, 2004]. We observed a new patient with a previously unrecognized finding. The patient is the third child born to nonconsanguineous phenotypically normal parents who belong to the same endogamous tribe in Saudi Arabia. She was born normally at 36-week gestation and weighed 2.8 kg. Soon after birth, she developed severe respiratory distress that needed immediate intensive care. The patient was referred to King Faisal Specialist Hospital and Research Center where she was diagnosed with congenital left upper lobar emphysema, with generalized minimal emphysematous changes. In addition, she was noted to have microtia, micrognathia, and small-beaked nose. She underwent left upper lobectomy in the first week of life, and subsequently she had surgical resection of right middle lobe. Histopathological report indicated markedly dilated alveolar spaces. The patient's general condition improved thereafter, though she still has hyperreactive airway disease. Chest radiographs showed variable infiltrates with small thymus. One of the films showed soft tissue density posterior to the lower end of the sternum, suggestive of Morgagni hernia. Thyroid function tests, random GH and IGF-1 performed in early life were all unremarkable. Somatomedin C (IGF-1) and random growth hormone (rGH) at 20 months of age showed 6.7 mU/L and 37 MCG/L, respectively. Same tests, repeated at age 6, showed IGF-1 at 87 µg/L (normal: 82–262 µg/L) and rGH at 0.76 mU/L (normal: 0–13 mU/L). GH stimulation test with Clonidine was safely performed in day and the patient was given an oral dose of Clonidine of 50 µg. Overall result showed definite GH deficiency (Table I). The patient was then started on recombinant GH on a weekly basis. The patient's motor and mental developments were within normal since the age of 2½ years. Currently, she is 10 years old, doing well at normal school. Her most recent evaluation showed an apparently intelligent girl with OFC 49cm (<5%), weight 18.5 kg (<5%), and height 117.5 cm (<5%). She is slender, has a small face, frontal bossing, high hairline, long beaked nose, hypoplastic alae nasi, micrognathia, large upper central incisors, dental malalignment with a wide space between the upper central incisors, and bilateral microtia (Fig. 1a,b). She also has hyperextensible joints, dislocatable elbows with palpable clicks. Tanner (sex maturity rating, SMR) was in a preadolescent stage. Examination of other organs was unremarkable. a: Patients full face, (b) profile showing microtia. Posterior and lateral radiograph of the knee joints showed absent patellae (Fig. 2). Hand radiograph for bone age showed retarded bone age (chronological age was 10 years, bone age according to Gruelich and Pyle standard is between 6 year 10 months and 7 years 10 months). Knee radiograph showing absent patella. Results of CT of the head, sonogram of abdomen/pelvis, and echocardiography were normal. Routine chromosomal analysis as well as FISH for 22q11 microdeletion was negative. The patient described here has classical manifestations of MGS, which include the triad of bilateral small ears, patellar aplasia/hypoplasia, and short stature. In addition, she has delayed bone age, which is another constant feature observed in almost all previous cases. Bongers et al. [2001], who described eight new patients and reviewed previously reported patients, found that MGS patients have a number of additional frequently encountered manifestations. These include microcephaly, small mouth, maxillary and mandibular hypoplasia, highly arched or cleft palate, and early feeding problems. Skeletal abnormalities, including slender long bones, abnormal glenoid fosse, dislocated radial heads, hook-shaped clavicles, thoracic and joint abnormalities, were also relatively common. Appearance of clitoromegaly, hypoplastic labia majora/minora, hypospadias, cryptorchidism, and hypoplasia of mammary glands have been noted also in a number of cases. No specific respiratory disorder had been noted previously, but early nonspecific respiratory problems were not uncommon. Our patient was presented in early life with congenital lobar emphysema. To our knowledge, it was the first instance of a defined respiratory problem described. In addition, the patient also had Morgagni hernia, which was another new finding in this syndrome. Short stature is a cardinal feature of MGS, observed in children and in adults. Few studies have documented variable results of endocrine work-up, including growth hormone assays. Loeys et al. [1999] reported two brothers with MGS, delayed bone age, one of whom was subjected to glucagon stimulation test with subnormal GH and borderline Somatomedin C. Cohen et al. [2002] reported on an 18.5-year-old patient that had severe proportionate short stature, and received recombinant GH therapy, though he has normal GH assay. They concluded that short stature was probably not related to growth hormone deficiency. Terhal et al. [2000] reported on two unrelated adolescent girls with MGS and both had breast hypoplasia, with regular menstrual periods. Endocrine work-up was entirely normal. In our patient, the stimulation test showed definite deficiency of GH while other endocrine work was normal. It is likely that the growth hormone deficiency is not the cause of short stature in MGS patients but possibly it contributes to the severity of growth deficiency later on in life and hence affects their ultimate height. Growth hormone supplementation was started, but it is too early to draw conclusions. We consider that it is important to regularly check growth hormone, including performing Clonidine stimulation tests in patients with MGS, on regular bases in the first years of life before puberty. To date, approximately 35 cases of this disorder have been published, from different ethnic groups. This patient is the first example of an Arab patient.
Introduction: To describe the clinical, radiological, histopathological features and outcome of Saudi children with infantile systemic hyalinosis (ISH) Methods: We retrospectively reviewed data of pediatric patients with ISH seen at a tertiary care hospital over 10 year period (1992–2002) Data included demographic characteristics, clinical manifestations, laboratory evaluation including biopsy, treatment and outcome. Results: Eighteen patients (10 male, 8 female) were diagnosed to have ISH. Fifteen patients (83.3%) presented in the neonatal period. The referral diagnosis was inaccurate in 12 patients (66.7%). Twelve patients were product of first degree consanguineous marriages and 5 families had more than one affected child. All patients had painful joint contractures and typical mucocutaneous changes (hyper-pigmented sclerodermatous skin over the knuckles and malleoli, gingival hyperplasia, subcutaneous and perianal nodules). Growth failure was noted in all of them and 39% had profuse diarrhea. 72% had low serum albumin. Radiological findings included osteopenia, periosteal reaction and osteolytic lesions. Tissue biopsy confirmed the diagnosis in 8 patients. Despite aggressive management with physiotherapy and different medications (including NSAIDs, penicillamine and methotrexate), the disorder was progressive and none of them showed improvement. Twelve patients died and 4 lost follow up and only 2 are alive. Conclusion: This report is the largest description of ISH. Our data support autosomal recessive inheritance and fatal disorder.
