Mutations in the prostaglandin transporter encoding gene SLCO2A1 cause primary hypertrophic osteoarthropathy and isolated digital clubbing.

Digital clubbing is usually secondary to different acquired diseases. Primary hypertrophic osteoarthropathy (PHO) is a rare hereditary disorder with variable digital clubbing as the most prominent feature, subperiosteal new bone formation, and arthropathy. Recently, mutations in the 15-hydroxy-prostaglandin dehydrogenase (15-PGDH) encoding gene HPGD were found to cause PHO. Here, we identified three unrelated families with different mutations in the prostaglandin transporter (PGT) encoding gene SLCO2A1 which presumably result in reduced metabolic clearance by 15-PGDH due to diminished cellular uptake of prostaglandin E(2) (PGE(2)) by mutant PGT. In two consanguineous families, homozygous mutations, an intragenic deletion that results in frameshift and a missense mutation, are associated with a severe PHO phenotype. In a third family, a heterozygous carrier of a stop mutation presents with isolated digital clubbing. Thus, our study further supports the importance of PGE(2) metabolism in the pathogenesis of digital clubbing and PHO.

An interesting case of pachydermoperiostosis with idiopathic myelofibrosis associated with monosomy 22.

A 24-year-old man was referred to our clinic in August 2003 with complaints of weakness, dizziness, and bilateral knee pain of 3 years' duration. Bilateral digital clubbing had been found on routine physical examination during his military service 4 years earlier. There were no cardiorespiratory or abdominal symptoms. There was no compromise in the activities of everyday life. The patient was not a chronic smoker. In the family history of the patient, his brother had been diagnosed with pachydermoperiostosis in another center 2 years earlier, but did not return to the hospital for a follow-up investigation of myelofibrosis. On physical examination, the patient showed marked drumstick clubbing of the hands (Fig. 1), and a pale general appearance. The causes of digital clubbing are shown in Table 1 (Fawcett RS, Linford S, Stulberg DL. Nail abnormalities: clues to systemic disease. Am Fam Physician 2004; 69: 1417-1424). Deep nasolabial folds were seen on the face. Skin hypertrophy, cutis verticis gyrata, and seborrhea on the face were also observed. The patient also complained of hyperhidrosis. Examination of the cardiovascular system was normal. There was bilateral swelling of the ankle and knee (Fig. 2). Hepatosplenomegaly was found on abdominal examination. Investigations showed hypochromic microcytic anemia [hemoglobin, 8.58 g/dL (normal, 12.2-18.1 g/dL); hematocrit, 28.1% (normal, 37.7-53.7%); white blood cell count, 3430/mm(3) (normal, 4600-10,200/mm(3)); neutrophils, 2470/mm(3) (normal, 2000-6900/mm(3)); lymphocytes, 820/mm(3) (normal, 600-3400/mm(3)); platelets, 162,000/mm(3) (normal, 142,000-424,000 mm(3)); mean corpuscular volume, 73.7 fL (normal, 80-97 fL)]. Anisocytosis, poikilocytosis, microcytosis, and hypochromia were observed on peripheral blood examination, and the erythrocyte sedimentation rate was 37 mm/h. The serum C-reactive protein level was 50.1 mg/L (normal, 0-5 mg/L). Biochemical parameters, including serum calcium, phosphate, alkaline phosphates and liver function tests, were found to be within the normal range. The causes of secondary hypertrophic osteoarthropathy associated with pulmonary, rheumatologic, endocrine, cardiac, and gastroenterologic disorders were excluded. Growth hormone level and thyroid function tests were normal. Antinuclear antibody, TORCH [Toxoplasma immunoglobulin M (IgM), rubella IgM, cytomegalovirus IgM, herpes simplex IgM] panel, and markers of hepatitis were negative. Serum Igs and rheumatoid factor were found to be within the normal range. There was subperiosteal new bone formation on bilateral knee X-ray (Fig. 3). Radiography of the chest, pulmonary function tests, arterial blood gas, and echocardiography were normal. Abdominal ultrasonography revealed hepatosplenomegaly. Amyloid deposition was not determined in rectal biopsy. Reticulin-type myelofibrosis was found on bone marrow biopsy (Figs 4 and 5). In the cytogenetic study, monosomy 22 was detected in four of 20 metaphase plates.

Clubbed fingers: the claws we lost?

Clubbed digits resemble the human embryonic fingers and toes, which look like the digits of a claw. Clubbed digits, thus, may represent the return of the embryonic claw and may even represent the claws man has lost during evolution, if ontogenesis really recapitulates phylogenesis. We put forward the hypothesis that secondary clubbing, like gynecomastia, is caused by a pathologic condition, which alters hormone levels in the blood, leading to the activation of 'dormant' genes, resulting in the development of an organ. However, the nature of the diseases that cause clubbing suggests that these hormones may actually be cytokines, acting as hormones. The nature of these cytokines is not known. They may be identified by comparing their blood levels or the combination of their blood levels to the presence or absence of clubbing, but also to the degree of clubbing and its disappearance after treatment of the primary disease.

[Clinical and molecular genetic observations on families with cherubism over three generations]. / Klinische und molekulargenetische Befunde bei Familien mit Cherubismus über 3 Generationen.

BACKGROUND: Cherubism is a rare fibro-osseous disorder that almost exclusively affects the maxilla and mandible. CASE REPORT: We report on three affected males in three generations in family A, and ten affected patients in family B. The youngest affected relative in family A also had craniosynostosis. His father and grandfather had cherubism and clubbed fingers. RESULTS AND DISCUSSION: Cherubism was mapped to region 4p16.3. Because of the associated craniosynostosis, we excluded the FGFR3 gene as a candidate gene for cherubism. The inheritance pattern is autosomal dominant with variable expression. The penetrance is 100% in males and 50-70% in females. We found incomplete penetrance in males, which does not conform with all publications.

[Keratosis palmoplantaris with clubbed fingers, hypotrichosis, hypohidrosis and dental dysplasia]. / Keratosis palmoplantaris mit Trommelschlegelfingern, Hypotrichose, Hypohidrose und Zahndysplasie.

A case of keratosis palmoplantaris with drumstick fingers, hypotrichosis, hypohidrosis and dental dysplasia is presented. Classification of this case among the more familiar syndromes of palmoplantar keratoderma is problematic.

[A case of Bamberger-Marie syndrome]. / Bamberger-Marie-syndroma esete.

Authors describe their case of Bamberger-Marie-syndrome, in which symptoms of the locomotor system were observed independently, without joined or basic disease. The relating literature is reviewed together with the pathological process in this rare disease.

[Palmar-plantar keratoderma and digital clubbing in 2 brothers]. / Cheratodermia palmo-plantare e ippocratismo digitale in due fratelli.

Two cases of clubbing of fingers and toes with congenital keratosis palmo-plantaris are reported. After a quick review of the factors involved in clubbing and keratoderma palmaris et plantaris, the inheritance tendency is discussed.

Clubbing and koilonychia.

Although some cases of spoon nails and clubbing are manifestations of internal disease, a significant number are completely idiopathic and of no consequence to the patient. Many patients have been forced to pay high insurance premiums or have been denied employment because of insignificant nail changes. When a patient has spoon nails or clubbing, a thorough but reasonable search for a primary etiology should be made. It should be recalled that when the complete syndrome of hypertrophic osteoarthropathy is present and joint pain is prominent, the possibility of a bronchogenic carcinoma is great. If a cause of spooning or clubbing is found, it should be treated. However, when the physician becomes satisfied that no associated disorder exists, he should reassure the patient. In the author's experience koilonychia is most commonly due to psoriasis, fungus, or trauma. It is hypothesized that the curvature changes in spoon and clubbed nails are the result of angulation of the nail matrix secondary to connective tissue changes. The structural hypothesis presented here is largely based on observations of congenital and traumatic deformities. These cases have allowed visualization of the angle of the nail matrix. Both spoon nails and clubbing are such definite reaction patterns that there must be some common mechanism for each deformity. Structural rules that should apply to the nail have been used. It is easy to think of multiple internal disorders producing the same connective tissue changes that alter the angle of the nail matrix. It is difficult to think of another mechanism by which internal disease could alter the bonds in hard keratin.

[Acro-coxo-mesomelic dwarfism: a new variety of autosomal recessive dwarfism]. / Le nanisme acro-coxo-mésomélique: variété nouvelle de nanisme récessif autosomique.

Acro-coxo-mesomelic dwarfism seems to be a new autosomal recessive entity, one compatible with survival. This severe, dysmorphic condition is characterized by shortening of median and distal segments of the limbs without anomalies of the spine. Other malformations are clubhand and foot, short malformed fingers, and reduced articular mobility of elbows and hips with radial and femoral dislocations. Skeletal X-rays show the following: delayed bone age; mesomelic shortening of the limbs with cubitus brevus, radius curvus, and mostly fibula agenesis; severe acromelic deformities with clinodactyly of the IIIrd, IVth, and Vth digits and brachyrhizophalangia of the IInd and Vth digits. Brachymetacarpia is diffuse, with a "squashed candle" appearance. The IInd metacarpals and the proximal phalanx of the Vth digits have a peculiar "butterfly wings" appearance. The toes are shortened with a "drumstick" appearance and phalangeal hypoplasia, mostly of the midphalanges; hip dislocation and dysplasia (coxomelic), with hypoplasia of the femoral head and a coxa vara cylindric neck.

Radial club hand. A continuing study of sixty-eight patients with one hundred and seventeen club hands.

Based on a review of the embryology, genetics, and anatomy of radial club hand, it is suggested that damage to the apical ectoderm on the anterior aspect of a developing limb bud leads to the deformity. Study of the families of thirty-five children with radial club hand suggested that the condition is not genetically patterned. The anatomical findings and associated congenital abnormalities in the cases known to be related to thalidomide and in those in which thalidomide was not a factor were similar except that the incidence of other skeletal deficiencies was higher in the thalidomide group. Thirty-one of the 117 radial club-hand deformities (in sixty-eight patients) under my personal supervision were treated by centralization of the carpus on the ulna with satisfactory improvement of the deformity. In three cases wrist deformity recurred mainly in a volar direction, apparently the result of muscle imbalance. No significant impairment of ulnar growth occurred and straightening of the wrist did not affect function adversely. Pollicization of the index finger was done on twenty-eight occasions. Although problems developed in the early cases, these can be avoided using the methods described and the operation can improve both function and appearance. A scheme of management is recommended.