Soliman et al. (2001) described the clinical, radiologic, and endocrine status of 8 children with pycnodysostosis. All patients had the characteristic phenotype of the disorder including short stature (8 of 8), increased bone density (7 of 8), separated cranial sutures (8 of 8), large fontanel with delayed closure (8 of 8), obtuse mandibular angle (8 of 8), delayed teeth eruption (8 of 8), enamel hypoplasia (7 of 8), dysplastic acromial ends of the clavicles (6 of 8), frontal bossing (6 of 8), ocular proptosis (8 of 8), and dysplastic nails (8 of 8). Developmental evaluation according to the revised Denever developmental screening showed normal motor, fine motor-adaptive language, and personal social abilities in all the children. All had normal hepatic and renal functions. Serum calcium and phosphorus concentrations were normal. Two children had low serum alkaline phosphatase concentration. Seven of the 8 children were born short (length standard deviation score [SDS] = -3 to -1.5). Deceleration of linear growth was significant during the first 3 years of life. All the children had height SDS below -3 at the end of their third year of life. Defective growth hormone (GH) secretion in response to provocation with clonidine and glucagon was found in 4 of the 8 patients. These 4 patients had pituitary hypoplasia on the magnetic resonance imaging (MRI) of their brain. In addition, 3 of these 4 patients had demyelination of the cerebrum. Patients with pycnodysostosis (n = 8) had low circulating concentrations of insulin-like growth factor-1 (IGF-1) compared with normal age-matched short children with constitutional short stature (CSS). IGF-I increased significantly after injecting GH for 3 days in these patients. Physiologic replacement with GH (18 U/m(2)/week) divided in daily evening doses subcutaneously increased IGF-1 concentration and improved linear growth velocity and height standard deviation scores (HtSDS) in the 4 children with GH deficiency.

Soliman et al. (1996) described the growth data and endocrine functions of four children and two parents with pycnodysostosis. They were followed up from birth every four to six months. Regular investigations were carried out which included complete hemogram, serum biochemistry, liver and renal function tests, ammonia and lactate, as well as their hormonal status. The levels of growth hormone and IGF-1 were measured with radioimmunometric assay. All children were born to consanguineous parents with normal apgar scores, with three of them being light for dates. They all had characteristic features of generalized increased bone density, separated cranial sutures, large fontanelle with delayed closure, delayed teeth eruption and short stature. Three had malapposed teeth, enamel hypoplasia was present in three, dysplastic acromial ends of the clavicles in three, Wormian bone pattern of the skull in two, frontal bossing in three, ocular proptosis in three, dystrophic nails in three, and only one had hepatosplenomegaly with moderate anemia. They all had normal motor development, fine motor-adaptive, language and personal-social abilities when assessed with the revised Denver developmental screening test. From the anthropometric measurements, it was found that the HtSDS correlated negatively with age as it decreased significantly with increasing age and all patients had HtSDS below -2 by the end of the first year, and below -3 by the end of their third year. Their BMI correlated with age, but at birth three children were born small for dates and their weight for length remained less than the tenth percentile throughout their early childhood years. Their bone age was delayed when compared to the chronological age, and CT scan of the hypothalamic-pituitary area revealed partial empty sella with mild cortical atrophy in one patient, but was otherwise normal in the others. All children had normal karyotype. As regarding the baseline investigations, they all had normal renal and hepatic functions, arterial blood gas, serum biochemistry, blood ammonia and lactate. Three children had normal hemoglobin but one of them who had a beta-thalasemia trait and partial red blood cell G6PD deficiency, was found to have anemia with reticulocytosis and hepatosplenomegaly. Hormonal analysis revealed normal glucose tolerance test, normal thyroid function test, and normal serum cortisol concentration, which excluded any abnormality of the hypothalamic-pituitary thyroid and adrenal axis in these patients. Normal gonadotrophins and testosterone levels were found in the adult patients, excluding any abnormality in the hypothalamic-pituitary-gonadal axis. Defective growth hormone secretion was found in three children and two fathers, even after clonidine and glucagon stimulation (peak was less than 7 microgram/l), as well as low IGF-1 concentrations which increased after growth hormone therapy for three days (excluding growth hormone resistance). The three children received growth hormone in daily subcutaneous doses, and after one year of treatment, their linear growth improved as shown by the increase of their height growth velocity and HtSDS along with an increase in the phosphate and alkaline phosphatase levels. Their bone age, however, was not affected.

Edelson et al. (1992) examined 14 cases of pycnodysostosis in a small Arab village with 3,000 inhabitants. They pictured 4 affected sibs, including fraternal male twins. An extensive pedigree was presented. The features that they pointed out included stress fractures of the tibia and femur, spondylolysis of L4 and L5, healed hangman's fracture of C2 (fracture of the pedicle), and a double row of teeth resulting from persistence of deciduous teeth. In the inbred Arab kindred reported by Edelson et al. (1992), Gelb et al. (1995) demonstrated by linkage analysis that the pycnodysostosis gene is located on 1q21. and found that 13 of 16 affected individuals were homozygous for the D1S305 allele, which had previously been assigned to the pericentromeric region of chromosome 1. Using markers flanking the centromere of chromosome 1, they localized the PKND locus to a region of about 4 cM between D1S442 and D1S305. D1S442 had previously been assigned to 1q21 by fluorescence in situ hybridization. They pointed to the interleukin-6 receptor (IL6R) and myeloid cell leukemia-1 (MCL1) as plausible candidate genes. IL6R induces the formation of osteoclasts and is highly expressed in osteoclasts from bone of patients with Paget disease and osteoarthritis.