Adult Chinese twins with Kenny-Caffey syndrome type 2: A potential age-dependent phenotype and review of literature.

Kenny-Caffey syndrome (KCS) type 2 (OMIM 127000) is a rare syndromic cause of hypoparathyroidism which is characterized by proportionate short stature, long bone abnormalities, delayed closure of anterior fontanelle, eye abnormalities, and normal intelligence. It is caused by variants in FAM111A (NM_001942519.1). In this review, we reported the first Chinese patients, a pair of monozygotic twins, with genetically confirmed KCS type 2 with over 20 years follow-up. We summarized the clinical features of 14 previously reported and genetically confirmed KCS type 2 patients; our twin patients exhibited a unique spinal manifestation which could be an important age-dependent feature of KCS type 2. In this review, over 60% KCS type 2 patients had dental problem and over 80% suffered from refractive errors or structural eye abnormalities. Therefore, early dental, ophthalmological, and orthopedic assessments are warranted for KCS type 2 patients. Micro-orchidism, previously reported in KCS type 2 patients, was also detected in our patients. The possibility of subfertility should be considered in male KCS type 2 patients. A multidisciplinary management approach for this rare syndrome is recommended.

Caffey disease: new perspectives on old questions.

The autosomal dominant form of Caffey disease is a largely self-limiting infantile bone disorder characterized by acute inflammation of soft tissues and localized thickening of the underlying bone cortex. It is caused by a recurrent arginine-to-cysteine substitution (R836C) in the α1(I) chain of type I collagen. However, the functional link between this mutation and the underlying pathogenetic mechanisms still remains elusive. Importantly, it remains to be established as to how a point-mutation in type I collagen leads to a cascade of inflammatory events and spatio-temporally limited hyperostotic bone lesions, and how structural and inflammatory components contribute to the different organ-specific manifestations in Caffey disease. In this review we attempt to shed light on these questions based on the current understanding of other mutations in type I collagen, their role in perturbing collagen biogenesis, and consequent effects on cell-cell and cell-matrix interactions.

Recurrence of infantile cortical hyperostosis: a case report and review of the literature.

OBJECTIVE: Also named Caffey disease, infantile cortical hyperostosis is a rare disease that usually affects children of a few weeks of age. The clinical picture is that of irritability, soft tissue swelling at various sites (mandible, clavicle, limbs) with local warmth, and pain on palpation. Radiographs demonstrate an important cortical thickening of the affected bony structures. There is generally spontaneous resolution of the inflammatory signs within the first few months or years of life, without future recurrence. We report the case of a recurrence in the adolescent period and conducted a thorough review of the literature to confirm this rare possibility. METHODS: We report the case of a 12-year-old female patient, presenting symptoms of pain and swelling of both forearms and legs, similar to her initial clinical picture at 1 month of age when the diagnosis of Caffey disease was made. Genetic analysis confirmed the COL1A1 mutation, the classic mutation described in the familial form of this disease. Radiologic investigation revealed new periosteal bone formation of the right and left ulnae and the left fibula, suggesting a recurrence of cortical hyperostosis. A thorough review of the literature was conducted, using the Medline database between 1948 and 2011, to confirm this hypothesis. RESULTS: The literature confirms the possibility but also the rarity of a recurrence of cortical hyperostosis in an adolescent who was diagnosed with Caffey disease in infancy. We have identified less than a dozen cases in the literature describing such a recurrence and in the majority there are no medical photographs or radiographs to support the clinical diagnosis. Our case is well documented both clinically and radiologically regarding the initial presentation and the recurrence in adolescence. CONCLUSIONS: Although very rare and poorly recognized, the diagnosis of recurrent cortical hyperostosis must be evoked in a patient who suffered from Caffey disease in infancy, and presents similar clinical characteristics in the adolescent period. LEVEL OF EVIDENCE: Level V--case report.

Caffey disease: an unlikely collagenopathy.

Infantile cortical hyperostosis (also known as Caffey disease) is characterized by hyperirritability, acute inflammation of soft tissues, and profound alterations of the shape and structure of the underlying bones, particularly the long bones, mandible, clavicles, or ribs. In this issue of the JCI, Gensure et al. undertook fine mapping of the genetic locus for this disease in a large kindred of individuals with the autosomal dominant form of the condition. The authors found a novel missense mutation in COL1A1, the gene encoding the alpha1 chain of type I collagen, in all affected individuals in 3 discrete pedigrees. This is a surprising finding, as all other reported mutations affecting the synthesis of type I collagen lead to conditions such as osteogenesis imperfecta and Ehlers-Danlos syndrome, in which quantitative or qualitative defects in type I collagen synthesis give rise to bone fragility and/or connective tissue hyperextensibility. The deleterious effect of the mutation on collagen fibril morphology is demonstrated; however, the precise functional link between the reported missense mutation and the localized inflammation and hyperostosis seen in Caffey disease awaits future studies.

A novel COL1A1 mutation in infantile cortical hyperostosis (Caffey disease) expands the spectrum of collagen-related disorders.

Infantile cortical hyperostosis (Caffey disease) is characterized by spontaneous episodes of subperiosteal new bone formation along 1 or more bones commencing within the first 5 months of life. A genome-wide screen for genetic linkage in a large family with an autosomal dominant form of Caffey disease (ADC) revealed a locus on chromosome 17q21 (LOD score, 6.78). Affected individuals and obligate carriers were heterozygous for a missense mutation (3040Ctwo head right arrowT) in exon 41 of the gene encoding the alpha1(I) chain of type I collagen (COL1A1), altering residue 836 (R836C) in the triple-helical domain of this chain. The same mutation was identified in affected members of 2 unrelated, smaller families with ADC, but not in 2 prenatal cases and not in more than 300 chromosomes from healthy individuals. Fibroblast cultures from an affected individual produced abnormal disulfide-bonded dimeric alpha1(I) chains. Dermal collagen fibrils of the same individual were larger, more variable in shape and size, and less densely packed than those in control samples. Individuals bearing the mutation, whether they had experienced an episode of cortical hyperostosis or not, had joint hyperlaxity, hyperextensible skin, and inguinal hernias resembling symptoms of a mild form of Ehlers-Danlos syndrome type III. These findings extend the spectrum of COL1A1-related diseases to include a hyperostotic disorder.

Patients with Van Buchem disease, an osteosclerotic genetic disease, have elevated bone formation markers, higher bone density, and greater derived polar moment of inertia than normal.

Van Buchem disease is an autosomal recessive disease characterized by overgrowth of the skeleton. In a group of Dutch patients the disease is thought to be due to a 52-kb deletion that results in decreased expression of the SOST gene. To further characterize the disease, the morphology of the metacarpals of six adult subjects and two juveniles with Van Buchem disease were measured on hand x-rays along with nine normal adults and nine adult carriers of the disease. Serum bone formation markers, alkaline phosphatase, type I procollagen peptide, and osteocalcin, and the urinary bone resorption marker, cross-linked N-telopeptide, were determined. Van Buchem patients had increased metacarpal outer diameter, inner diameter, cortical thickness, and bone mineral density. Calculated bone volume and derived polar moment of inertia were markedly elevated (elevations of 158 +/- 33% and 497 +/- 95%, respectively) consistent with increased bone strength. Serum procollagen peptide and osteocalcin were significantly higher in Van Buchem patients. Urinary cross-linked N-telopeptide was significantly elevated in Van Buchem patients. None of these changes was found in Van Buchem carriers. These observations indicate that decreased expression of the SOST gene can lead to increased bone formation and to stronger bones.

Antenatal-onset infantile cortical hyperostosis and nonimmune hydrops.

Infantile cortical hyperostosis antenatal onset is an uncommon disease characterized by polyhydramnios, anasarca or hydrops, pulmonary hypoplasia, hepatomegaly, bowed hyperostotic long bones, and a poor prognosis. Sonographically the intrauterine manifestations may be similar to those of osteogenesis imperfecta, type II.

Facial paralysis at the age of 2 months as a first clinical sign of van Buchem disease (endosteal hyperostosis).

In this paper we report a 7.5-year-old physically normal boy with van Buchem disease (endosteal hyperostosis). Vague complaints of headache were the indication for X-ray examination. At the age of 2 months a left-side peripheral facial nerve palsy suddenly occurred in this boy. Skull X-rays gave normal results at that age, suggesting that encroachment of the cranial nerves in van Buchem disease may occur as early as in the postnatal period, even before sclerosis of the skull has become radiologically visible.

Unusual cause of short stature.

A 24-year-old man evaluated for paresthesias and short stature was found to be hypocalcemic on initial presentation. Further evaluation showed that he had a low-normal parathormone level by amino-terminal assay, medullary stenosis of the long bones, and multiple ophthalmologic abnormalities. The remainder of his pituitary function, including growth hormone response to insulin-induced hypoglycemia, was normal. As no family history of similar findings was evident, a sporadic case of Kenny's or Kenny-Caffey syndrome was diagnosed. He became normocalcemic in response to vitamin D and calcium carbonate therapy. The results of testing in this patient and the findings in other patients previously described with the Kenny-Caffey syndrome are reviewed.