Overlapping phenotype comprising Kenny-Caffey type 2 and Sanjad-Sakati syndromes: The first case report.

Kenny-Caffey syndrome (KCS) is a rare hereditary skeletal disorder involving hypoparathyroidism. The autosomal dominant form (KCS2), caused by heterozygous pathogenic variants in the FAM111A gene, is distinguished from the autosomal recessive form (KCS1) and Sanjad-Sakati syndrome (SSS), both caused by pathogenic variants in the tubulin folding cofactor E (TBCE) gene, by the absence of microcephaly and intellectual disability. We present a patient with KCS2 caused by a de novo pathogenic variant c.1706G>A (p.Arg569His) in FAM111A gene, presenting intellectual disability and microcephaly, which are considered to be typical signs of SSS. We suggest that KCS1, KCS2, and SSS may not represent mutually exclusive clinical entities, but possibly an overlapping spectrum.

Fetuin-A deficiency is associated with infantile cortical hyperostosis (Caffey disease).

BACKGROUND: Infantile cortical hyperostosis (ICH)/Caffey disease is an inflammatory collagenopathy of infancy, manifested by subperiosteal bone hyperplasia. Genetically, ICH was linked with heterozygosity for an R836C mutation in the COL1A1 gene. Although an autosomal-recessive trait is also suspected, it has not been proven thus far. METHODS: A case of an infant male born to consanguineous parents is reported, presenting with classical findings, course, and clinical outcome of ICH. Whole-exome sequencing (WES) was performed in order to identify a possible underlying genetic defect. RESULTS: WES analysis revealed a novel homozygous nonsense mutation in lysine 2 of fetuin-A, encoded by the ALPHA-2-HS-GLYCOPROTEIN (AHSG) gene (c.A4T; p.K2X). Fetuin-A is an important regulator of bone remodeling and an inhibitor of ectopic mineralization. By enzyme-linked immunosorbent assay (ELISA), we show a complete deficiency of this protein in the patient's serum, compared to controls. CONCLUSION: A novel homozygous nonsense mutation in AHSG gene has been found in ICH patient with a typical phenotype, resulting in fetuin-A deficiency. This finding postulates an autosomal-recessive mode of inheritance in ICH, which, unlike the autosomal-dominant inheritance associated with COL1A1, is associated with AHSG and fetuin-A deficiency.

Case Report of Worth Syndrome and Chiari I Malformation: Unusual Association and Surgical Treatment.

BACKGROUND: Worth syndrome or autosomal dominant endosteal hyperostosis (ADEH) is an extremely rare genetic disease involving increased bone density. To the author's knowledge, this is the second case report of a family with neurologic involvement associated with this condition along with its surgical treatment. The most effective treatment for clinically significant neurologic symptoms in this scenario is currently unknown, and there is sparse experience on surgical treatment for this condition reported in the literature. Therefore we aim to make a contribution to the identification of a standard and consistently successful surgical management. CASE DESCRIPTION: Two patients, mother (Patient 1) and daughter (Patient 2), were diagnosed with Worth syndrome. Both presented with the typical facial characteristics described for ADEH. Interestingly, Patient 1 presented the novel mutation in the LRP5 gene that is associated with different conditions involving increased bone density. Although neurologic symptoms are infrequent in ADEH, both referred chronic headache, nausea, and vomiting. Neuroimaging showed an increased cranial bone density and Chiari I malformation. The patients underwent a midline suboccipital craniectomy with excision of the posterior arch of C1 and duroplasty. However, due to a symptomatic recurrence 5 years after surgery, Patient 1 was reoperated on. We extended the craniectomy and also carried out a C2 laminectomy. CONCLUSION: After surgical interventions, patients' neurologic symptoms were successfully resolved. This report shows that posterior fossa decompression including duroplasty may be a valid treatment option in case of neurologic involvement.

Síndrome de Caffey-Silverman / Caffey-Silverman syndrome

La enfermedad de Caffey o síndrome Caffey-Silverman es una enfermedad poco común, con una incidencia en torno a 48/100.000 recién nacidos vivos, caracterizada por un crecimiento anómalo y deformidad de huesos largos, siendo los más afectados, la mandíbula, parrilla costal y cúbito. En su forma más común, el desarrollo de la patología se produce a partir del segundo mes de vida. Su cuadro clínico característico consiste en un aumento y tumefacción de partes blandas, fiebre, hiperirritabilidad y dolor. Los estudios de imagen revelan un crecimiento subperióstico masivo, que habitualmente se resuelve de forma espontánea en torno a los dos años de vida, sin dejar habitualmente ninguna secuela objetivable. Existen otras formas más agresivas, aunque son menos comunes. El tratamiento en la forma autolimitada es sintomático (antipiréticos, analgésicos) y su manejo es conservador. Presentamos el caso de una lactante, en seguimiento en nuestro centro, con diagnóstico de enfermedad de Caffey (AU)

Caffey disease, or Caffey-Silverman syndrome, is a very uncommon illness with an incidence of 48/100,000 live newborns. It is characterised by an anomalous formation and deformity of long bones and typically also involves the mandible, ribs and ulnar bone. In the most common form, onset usually occurs around the age of 2 months. Frequent symptoms are fever, painful swelling of soft tissues, fever, irritability and general pain. Imaging studies show massive subperiosteal new bone formation that spontaneously resolves by the age of 2 years, normally with no apparent sequels. There are other severe forms of this disease but their incidence is much lower. Treatment of the most common form of Caffey disease is symptomatic (antipyretics and anti-inflammatory drugs). We report a case of Caffey disease in an infant who is under follow-up in our hospital (AU)

An Unusual Cause of Pseudopapillary Oedema: Hyperphosphatemic Hyperostosis Syndrome.

For the first time, we report hyperphosphatemic hyperostosis syndrome as a cause for pseudopapillary oedema in a pediatric case. Clinical findings are presented and discussed with tomographic evaluation (optical coherence tomography and Heidelberg retinal tomography) of optic discs, visual-evoked potentials, and visual fields.

Root anomalies and dentin dysplasia in autosomal recessive hyperphosphatemic familial tumoral calcinosis (HFTC).

Hyperphosphatemic familial tumoral calcinosis (HFTC, OMIM #211900) is an autosomal recessive metabolic disorder characterized by hyperphosphatemia, tooth root defects, and the progressive deposition of calcium phosphate crystals in periarticular spaces, soft tissues, and sometimes bone.(1) In this HFTC case report, we document the dental phenotype associated with a homozygous missense mutation (g.29077 C>T; c.484 C>T; p.Arg162*) in GALNT3 (OMIM 6017563), a gene encoding UDP-GalNAc transferase 3 that catalyzes the first step of O-linked oligosaccharide biosynthesis in the Golgi. The medical and dental pathology is believed to be caused primarily by high serum phosphate levels (hyperphosphatemia), which, in turn, is caused by failure of GALNT3 to glycosylate the phosphate regulator protein FGF23, impairing its ability inhibit reabsorption of filtered phosphate in the kidneys.

Hyperphosphatemic familial tumoral calcinosis: odontostomatologic management and pathological features.

BACKGROUND: Hyperphosphatemic familial tumoral calcinosis (HFTC) is to a rare autosomal recessive disorder characterized by cutaneous and sub-cutaneous calcified masses, usually adjacent to large joints. The aim of the current study was to report on the clinico-pathological features of a patient with HFCT, with emphasis on alterations in the jawbones and teeth and the subsequent therapeutic interventions. CASE REPORT: A 13-year-old male patient with HFTC diagnosis came to our attention for dental anomalies and maxillary and mandibular hypoplasia. OPT highlighted multiple impacted teeth, short and bulbous teeth, and pulp chamber and canal obliterations. Lateral cephalometric radiograms pointed out retrusion of both jaws, skeletal class II malocclusion, and deep-bite. He underwent orthopedic, orthodontic, conservative, and surgical treatments, allowing the correction of maxillo-facial and dental abnormalities and dysmorphisms without adverse effects. The surgical samples were sent for conventional and confocal laser scanning microscope (CLSM) histopathological examination, which highlighted several metaplastic micro- and macro-calcifications in the soft tissues, and typical islands of homogenous, non-tubular, dentino-osteoid calcified structures in dentinal tissues. CONCLUSIONS: The management of maxillo-facial abnormalities in patients affected by HFTC is very difficult and, requires a combined therapeutic approach. To date, very few indications have been published in the literature.

Severe vascular calcification and tumoral calcinosis in a family with hyperphosphatemia: a fibroblast growth factor 23 mutation identified by exome sequencing.

BACKGROUND: Tumoral calcinosis is an autosomal recessive disorder characterized by ectopic calcification and hyperphosphatemia. METHODS: We describe a family with tumoral calcinosis requiring amputations. The predominant metabolic anomaly identified in three affected family members was hyperphosphatemia. Biochemical and phenotypic analysis of 13 kindred members, together with exome analysis of 6 members, was performed. RESULTS: We identified a novel Q67K mutation in fibroblast growth factor 23 (FGF23), segregating with a null (deletion) allele on the other FGF23 homologue in three affected members. Affected siblings had high circulating plasma C-terminal FGF23 levels, but undetectable intact FGF23 or N-terminal FGF23, leading to loss of FGF23 function. CONCLUSIONS: This suggests that in human, as in experimental models, severe prolonged hyperphosphatemia may be sufficient to produce bone differentiation proteins in vascular cells, and vascular calcification severe enough to require amputation. Genetic modifiers may contribute to the phenotypic variation within and between families.

Caffey disease in neonatal period: the importance of the family!

A male newborn was apparently well until his second day of life, when increased irritability and a swelling in his right leg were noted. He was rooming-in with his mother since birth. On examination, a mass on the anterior surface of the right leg was noticed. The mass was firm, elongated, ill-defined, unmovable and painful at palpation. No overlying skin changes were seen. The newborn had a family history of neonatal bone swelling with resolution before the age of 2. Subsequent images showed hyperostosis in the diaphysis of the right tibia. After exclusion of other conditions such as trauma, osteomyelitis and congenital syphilis, the involvement of the tibial diaphysis, sparing the epiphyses and the benign course of the disease in family history, were indicative of Caffey disease. The genetic study confirmed this diagnosis. Caffey disease, although rare, should not be overlooked in the diagnostic approach to childhood bone swelling.

Tumoral calcinosis of the cervical spine and its association with Caffey disease in a 4-month-old boy: case report and review of the literature.

Tumoral calcinosis (TC) is a rare condition involving large joints and rarely the spine. It is characterized by calcification and swelling of periarticular tissues. Caffey disease (CD) is defined by recurrent episodes of painful soft tissue swelling and cortical thickening of the underlying bones. It is a self-limited disease that occurs in the first year of life. We report the first association of CD and TC of the cervical spine in a 4-month-old boy. We suggest that TC occurred as a consequence of the repetitive reparative process that takes place in CD, adding the latter to the list of diseases that may secondarily produce TC.

Pseudopapilledema in Kenny-Caffey syndrome.

A 21-year-old man with Kenny-Caffey syndrome had been observed since 1993 for hyperopia. Fundus examination revealed swollen optic disks. Further examinations (fluorescein angiography, B-scan ultrasonography, and optical coherence tomography) confirmed the optic nerve head elevation. The authors report a rare case of Kenny-Caffey syndrome with extreme pseudopapilledema. Although uncommon, ophthalmologists should be mindful of this disorder when a patient presents with characteristic findings because severe electrolyte disturbances may complicate the clinical course.