A Rare Cause of Hypophosphatemia: Raine Syndrome Changing Clinical Features with Age.

Raine Syndrome (RS) is caused by biallelic loss-of-function mutations in FAM20C gene and characterized by hypophosphatemia, typical facial and skeletal features. Subperiosteal bone formation and generalized osteosclerosis are the most common radiological findings. Here we present a new case with RS. A 9-month-old male patient on a home-type ventilator was referred for hypophosphatemia. He was born with a weight of 3800 g to non-consanguineous parents. Prenatal ultrasound had demonstrated nasal bone agenesis. A large anterior fontanel, frontal bossing, exophthalmos, hypoplastic nose, high arched palate, low set ears, triangular mouth, and corneal opacification were detected on physical examination. Serial skeletal X-rays revealed diffuse osteosclerosis at birth which was gradually decreased by the age of 5 months with subperiosteal undermineralized bone formation and medullary space of long bone could be distinguishable with bone-within-a-bone appearance. At 9 months of age, hand X-ray revealed cupping of the ulna with loose radial bone margin with minimal fraying and osteopenia. Cranial computed tomography scan showed bilateral periventricular calcification and hydrocephalus in progress. The clinical, laboratory, and radiological examinations were consistent with RS. Molecular analyses revealed a compound heterozygous mutation in FAM20C gene (a known pathogenic mutation, c.1645C > T, p.Arg549Trp; and a novel c.863 + 5 G > C variant). The patient died due to respiratory failure at 17 months of age. This case allowed us to demonstrate natural progression of skeletal features in RS. Furthermore, we have described a novel FAM20C variant causing RS. Previous literature on RS is also reviewed.

Mutations in LONP1, a mitochondrial matrix protease, cause CODAS syndrome.

Cerebral, ocular, dental, auricular, skeletal anomalies (CODAS) syndrome (MIM 600373) was first described and named by Shehib et al, in 1991 in a single patient. The anomalies referred to in the acronym are as follows: cerebral-developmental delay, ocular-cataracts, dental-aberrant cusp morphology and delayed eruption, auricular-malformations of the external ear, and skeletal-spondyloepiphyseal dysplasia. This distinctive constellation of anatomical findings should allow easy recognition but despite this only four apparently sporadic patients have been reported in the last 20 years indicating that the full phenotype is indeed very rare with perhaps milder or a typical presentations that are allelic but without sufficient phenotypic resemblance to permit clinical diagnosis. We performed exome sequencing in three patients (an isolated case and a brother and sister sib pair) with classical features of CODAS. Sanger sequencing was used to confirm results as well as for mutation discovery in a further four unrelated patients ascertained via their skeletal features. Compound heterozygous or homozygous mutations in LONP1 were found in all (8 separate mutations; 6 missense, 1 nonsense, 1 small in-frame deletion) thus establishing the genetic basis of CODAS and the pattern of inheritance (autosomal recessive). LONP1 encodes an enzyme of bacterial ancestry that participates in protein turnover within the mitochondrial matrix. The mutations cluster at the ATP-binding and proteolytic domains of the enzyme. Biallelic inheritance and clustering of mutations confirm dysfunction of LONP1 activity as the molecular basis of CODAS but the pathogenesis remains to be explored.

Infantile loss of teeth: odontohypophosphatasia or childhood hypophosphatasia.

Hypophosphatasia is a hereditary disorder characterized by a deficiency of serum and bone alkaline phosphatase (ALP) activity and defective skeletal mineralization. It is caused by a loss of function mutations in the tissue nonspecific ALP gene (TNSALP) encoding the tissue nonspecific alkaline phosphatase. A 4-year-and-8-month-old girl presented with premature exfoliation of the anterior incisors and canines. Very low ALP level (27 IU/ml) suggested the diagnosis of hypophosphatasia, which was supported by an elevated urine phosphoethanolamine/Cr of 84 µmol/mmol (reference range, <25 µmol/mmol) and serum pyridoxal-5'-phosphate of 393 µg/L (reference range, 3.6-18 µg/L). The phenotype of the patient was subsequently classified as mild childhood hypophosphatasia. TNSALP gene sequencing revealed the homozygous c.382 G > A (p.V128M) mutation. This mutation was previously observed in a series of patients with severe hypophosphatasia, pointing out the possible role of other genetic or environmental factors in the modulation of the hypophosphatasia phenotype.

The prevalence and risk factors of premature thelarche and pubarche in 4- to 8-year-old girls.

AIM: To assess the prevalence of premature thelarche (PT) and pubarche in healthy 4- to 8-year-old girls and to investigate factors associated with early pubertal development. METHOD: Eight hundred and twenty girls were examined by two paediatric endocrinologists to determine Tanner staging. The effects of body mass index, gestational age, intrauterine growth status, age at the first tooth eruption, socio-economical status, maternal age of menarche and consumption of certain food items on early pubertal development were analysed through parametric and nonparametric tests. RESULTS: The prevalence of PT and of premature pubarche was 8.9% and 4.3%, respectively. We found a strong association between the prevalence of PT and the body mass index standard deviation scores (BMI SDS). There were more girls with BMI SDS values above 1 in the PT group (56.1%) than among the remaining subjects (22.9%). Premature thelarche was not significantly associated with intrauterine growth, premature birth, socioeconomic status, age of first tooth eruption or maternal age of menarche. Similarly, the amount of milk, eggs, chicken or fish consumed was not associated with PT. None of the investigated factors were associated with premature pubarche. CONCLUSION: Occurrence of PT is strongly associated with BMI SDS. Studies investigating secular trends in pubertal development must consider a secular change in body mass index.

Identification of a novel dentin matrix protein-1 (DMP-1) mutation and dental anomalies in a kindred with autosomal recessive hypophosphatemia.

An autosomal recessive form of hypophosphatemia (ARHP) was recently shown to be caused by homozygous mutations in DMP1, the gene encoding dentin matrix protein-1 (DMP-1), a non-collagenous bone matrix protein with an important role in the development and mineralization of bone and teeth. Here, we describe a previously not reported consanguineous ARHP kindred in which the three affected individuals carry a novel homozygous DMP-1 mutation. The index case presented at the age of 3 years with bowing of his legs and showed hypophosphatemia due to insufficient renal phosphate retention. Serum alkaline phosphatase activity was elevated, with initially normal PTH. FGF23 was inappropriately normal at an older age while being treated with oral phosphate and 1,25(OH)(2)D. Similar clinical and biochemical findings, except for elevated FGF23 levels, were present in his 16-month-old brother and his 12.5-year-old female cousin; the parents of the three affected children are first-degree cousins. Nucleotide sequence analysis was performed on PCR-amplified exons encoding DMP-1 and flanking intronic regions. A novel homozygous frame-shift mutation (c.485Tdel; p.Glu163ArgfsX53) in exon 6 resulting in a premature stop codon was identified in all effected individuals. The parents and available unaffected siblings were heterozygous for c.485Tdel. Tooth growth and shape were normal for the index case, his affected brother and cousin, but their permanent and deciduous teeth displayed enlarged pulp chambers. The identified genetic mutation underscores the importance of DMP-1 mutations in the pathogenesis of ARHP. Furthermore, DMP-1 mutations appear to contribute, through yet unknown mechanisms, to tooth development.