Digital Clubbing, Isolated Congenital

A number sign (#) is used with this entry because of evidence that isolated congenital digital clubbing can be caused by homozygous mutation in the 15-hydroxyprostaglandin dehydrogenase gene (HPGD; 601688) on chromosome 4q34.

Description

Digital clubbing is characterized by enlargement of the nail plate and terminal segments of the fingers and toes, resulting from proliferation of the connective tissues between the nail matrix and the distal phalanx (Myers and Farquhar, 2001).

Clinical Features

Weber (1919) reported 2 unrelated families and 1 unrelated individual with isolated clubbing of the digits. One family involved 2 otherwise healthy 25-year-old twin brothers who had clubbing of all digits in both hands; the toes were not affected. Their 30-year-old brother was said to have the same changes of the fingers, but their mother did not; their father was deceased. The proband of the second family was an otherwise healthy 25-year-old Irishman who had bilateral 'incurved nails' with clubbing of the fingers and toes 'ever since he could remember.' His father, 3 of his brothers, and 1 of his sisters were also said to have the condition. In addition, the author examined a 46-year-old man with psoriasis who had 'typical clubbing' of all his fingers, but not his toes, 'ever since he could remember;' no cause was found for the clubbing.

Horsfall (1936) described 20 affected individuals from 3 unrelated multigenerational families with clubbing of the fingers, 10 of whom also had clubbing of the toes; all reported that the abnormality had been present from birth and remained fixed in degree with no progression or regression. The author examined 10 affected individuals, but found no organic lesion sufficient to account for the clubbing. The clubbing was uniformly in the form of a distal digital 'drumstick' or 'club-like enlargement' that was symmetric and bilateral, with the most extensive clubbing in the thumbs and great toes. In 2 affected females who were examined, not all digits were affected: both had bilateral involvement of the thumbs but sparing of the other fingers, and one had involvement only of the second and fourth toes, whereas in the other only the great toes were affected. X-rays of the hands and feet of the 3 probands revealed that the clubbing was apparently due to an increase in the soft tissues; there was also slight broadening of the tips of the terminal phalanges in 2 probands, but this was deemed insufficient to account for the clubbing, and the third proband had no bony changes. The author stated that there were no qualitative differences between the clubbing seen in these families and the clubbed fingers associated with pulmonary tuberculosis, lung abscess, bronchiectasis, and congenital heart disease, except for occasional cyanosis present in the latter group. Horsfall (1936) concluded that congenital clubbing is an inherited disorder that does not appear to be sex-linked.

Fischer et al. (1964) reviewed both disease-associated and isolated congenital acropachy (clubbing) and reported 2 unrelated families with inherited clubbing. The first family involved white 21-year-old twin brothers who had symmetric clubbing of all fingers and the first and second toes, with the nail plate forming an angle of almost 180 degrees with the phalanx in affected digits. Physical examination was otherwise normal, and x-rays of the chest, hands, wrists, ankles, and feet were normal. The twins' paternal uncle also had symmetric clubbing of the fingers and toes, and their father and paternal grandmother were said to have marked clubbing of the fingers and toes. The proband of the second family was a 19-year-old black male who presented for evaluation of enlarged terminal digits of his hands and feet, particularly the thumbs and great toes, which he said had begun to enlarge 8 years previously at about the onset of puberty. He was healthy and examination was otherwise normal. Investigation of his family revealed that 11 of 24 paternal relatives and 6 of 12 maternal relatives were also affected; none had significant cardiopulmonary, hepatic, or gastrointestinal disease. The clubbing was generally first noted during puberty and progressed through adolescence and the early twenties and then stabilized; it never regressed. Of 7 prepubertal children examined, 4 had definite evidence of minimal clubbing. The clubbing in the maternal and paternal relatives, though prominent, was not as marked as in the proband, suggesting that he might be homozygous for the condition. In both families, the pattern of segregation suggested sex-limited autosomal dominant inheritance, with low penetrance for females.

McKusick (1966) noted that familial clubbing might be more frequent in blacks than in whites, and that there was some uncertainty as to whether it was distinct from pachydermoperiostosis (167100). However, he stated that 'a particularly striking example of clubbing in a black father and 2 sons without accompanying features of pachydermoperiostosis leaves no doubt in my mind of the reality of this entity.'

Diagnosis

Myers and Farquhar (2001) analyzed 16 published reports of digital clubbing in which quantitative or qualitative assessment was described. The authors stated that clubbing, which is almost always painless, is caused by proliferation of connective tissue between the nail matrix and the distal phalanx, resulting in a nail-bed thickness of greater than 2.0 mm and a lower density of nail-bed connective tissue. On palpation of the base of the nail bed, there is 'sponginess' and the nail can appear to be 'floating' within the soft tissue. Myers and Farquhar (2001) recommended the use of the profile angle and phalangeal depth ratio as quantitative indices in identifying clubbing, and stated that when those values exceed 180 degrees and 1.0, respectively, clinical judgment must be exercised in determining the extent of further evaluation for underlying disease.

Mapping

Tariq et al. (2009) performed linkage analysis in a 6-generation consanguineous Pakistani family with isolated congenital clubbing, in which 11 affected members (4 males and 7 females) had bilateral symmetric clubbing in all fingernails and toenails with no associated abnormalities. Genomewide mapping revealed that all affected individuals were homozygous at marker D4S2368 on chromosome 4q32.3, where a maximum 2-point lod score of 2.98 (theta = 0.0) was obtained; a maximum multipoint lod score of 3.62 was achieved at several markers along the disease interval. Recombination events defined a 12.27-Mbp (13.25-cM) critical interval flanked by markers D4S2952 and D4S415.

Molecular Genetics

In a 6-generation consanguineous Pakistani family with isolated congenital clubbing mapping to chromosome 4q32.3, Tariq et al. (2009) sequenced 10 candidate genes and identified homozygosity for a missense mutation in the HPGD gene (S193P; 601688.0004) in affected individuals. Obligate carriers were heterozygous for the mutation, which was not found in 300 ethnically matched chromosomes.