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Study of non-syndromic thumb aplasia in six independent cases.

Byline: Hafiza Fizzah Riaz Karmoon Lal Bashir Ahmad Muhammad Shuaib Syeda Farwa Naqvi and Sajid Malik

: ABSTRACTObjectives: To report on six independent and isolated cases demonstrating thumb aplasia as an essentially limb-specific phenotype.Methods: The subjects were ascertained during 2011-2013 from six different geographic regions of Pakistan and underwent detailed clinical and phenotypic examination.Results: The affected arms of patients had complete absence of first digital rays medial inclinations of second and fifth fingers narrowing of palms missing carpals and shortening of zeugopod. All the subjects were presented with isolated and sporadic limb deficiencies and five had no family history of limb or any other malformation. Parental consanguinity was denied in majority of the cases. We present detailed phenotypic manifestation of thumb apalsia in these subjects.Conclusion: Thumb aplasia markedly impairs the normal function of affected hand. Surgical procedures like pollicisation of the index finger should be employed to improve the quality of life of these subjects. There is so far no specific genetic factor known for isolated thumb aplasia compromising an accurate genetic counseling. Collection of patients with similar phenotypic presentations could be useful in further molecular genetic investigations.

KEY WORDS: Absence deformity Absent digit Oligodactyly Limb anomaly Limb defects Thumb aplasia Pakistani subjects.INTRODUCTION

Congenital reduction of thumb is a relatively heterogeneous malformation of first digital ray (OMIM-188100)12 The condition ranges from hypoplastic thumb to a complete absence of first digit and its components.3 The variation in the clinical presentation of hypoplastic thumb has lead to the suggestion of their anatomical categorization into five entities which depict increasing severity of thumb deficiency.45 Complete reduction of first digit classified as type V is a rare malformation and was observed to be 0.25/10000 births.6 It occurs more often in males than in females and is bilateral in about two-third of the cases.235 Most of the isolated cases of absent thumb are sporadic. For the familial cases an autosomal dominant inheritance is witnessed particularly the types associated with

other anomalies.12 The most common association is radial deficiency of varying degrees.35 Thumb agenesis accompanies Holt-Oram syndrome (OMIM-142900) VACTERL association (OMIM-192350) phocomelia Seckel syndrome (OMIM-210600) thrombocytopenia-absent radius syndrome(OMIM-274000) Fanconi anemia (OMIM-227650)and Duane-radial ray syndrome (OMIM-607323). Inmajority of these syndromes cardiac renal skeletalocular and hematological organs are involved.1Mutations in various genes like FANCE SF3B4WNT7A and ATR have been implicated in Fanconianemia acrofacial dysostosis-1 fibular aplasia withpoly-syn-oligodactyly and Seckel syndrome-1respectively suggesting their likely role in thumbpathomorphogenesis.1Data on limb dysmorphology are scarce for thePakistani patients.78 Here we report on six differentcases with thumb agenesis presented as a limb-specific phenotype.

SUBJECTS

Six patients (4M 2F) with thumb deficiencies were recruited during 2011-2013 from various geographic regions/medical institutes across Pakistan (Table-I). An informed consent was obtained from each individual or his/her parents. Detail of socio-demographic and biological parameters were obtained. Pedigrees up to three generations were constructed to rule out history of any congenital anomaly and to ascertain the mode of inheritance. Parental marriage types were documented and inbreeding coefficient (F) was calculated in order to account for a likely recessive inheritance. Clinical data with respect to the limb were acquired accordingly and general medical examination involving vital organs was performed. Photographs of affected hands of all subjects and radiographs of two subjects were obtained. Cases were classified according to the revised scheme of hypoplastic thumb by Blauth and Schneider- Sickert4 and James et al.5The socio-demographic and biological attributes of the recruited cases including parental consanguinity sibship composition and family history of any congenital malformation are mentioned in Table-I. The key presentation in all cases was thumb aplasia. Following are the key clinical findings in the recruited patients (summarized in Table-II).Case I: The patient was a 45 year house-wife belonging to a rural area (Table-I). There was parental consanguinity (inbreeding coefficient F=0.0625) and she had five unaffected sibs. She herself had a non-consanguineous union (F=0.0156) and had five normal offspring. On physical examination she was observed to have bilateral and symmetrical aplasia of thumbs (Fig. 1A). Index fingers were medially deviated. There was evidence of clinodactyly in the left hand. Additionally both

Table-I: Socio-demographic and biological attributes of patients with thumb aplasia.

VariablePatient

###I###II###IIIVI V VI

Gender (M F)###F###M###M###F###M###M

Age (year)###45###6###6###3###7###26

Geographic origin (Pakistan)###South Punjab Interior Sindh South KPK South KPK North KPK South KPK

Rural/Urban###R###R###U###U###R###R

Caste###Arain###Hindu/Bheel Pathan###Pathan###Yousafzai###Mughal

Language/ethnicity###Punjabi###Marwari###Pashto###Pashto###Pashto###Pashto

Socio-economics###Low###Poor###Low-middleLow-middle Poor###Low

Family/house-hold type###Nuclear###Nuclear###Extended Extended###Extended###Nuclear

Education/occupation###Nil/###Nil###Student###Nil###Nil###Intermediate/

###house wife###technical job

Marital status###Married###Single###Single###Single###Single###Single

Parental Consanguinity###FC###UR###UR###FC###UR###UR

Father age at patient's birth (year)###23###34###26###27###35###39

Mother age at patient's birth (year)###20###30###23###22###32###35

Patient's parity###3 of 6###7 of 8###2 of 3###1 of 2###4 of 5###4 of 6

No. of normal sibs (B:S)###3:2###3:5###2:0###1:0###2:2###3:2

Family history of limb defect###No###No###No###Yes###No###No

Table-II: Phenotypic manifestation of thumb aplasia in the recruited patients.

###Phenotype###Patient

###I###II IIIVIV###VI

###Absent thumb###Both###Both Left Left Right; left mild hypoplastic Left

###Index finger medial inclination###R+ L++###R+ L+###R++###L+

###Other digits###L. clinodactyly###5th###5th clinodactyly###5th digits

###of 5th###digit small###small

###Palm thin/reduced###R+ L+###L+###L+###L+###R+###L+

###Arm reduced/short###R+ L+###R+ L+ L+###L++ R++###L+

arms were slightly short in size (Table-II). The subject was well-adopted to perform her routine house- hold activities. Roentgenographic study revealed that first digital ray along with its components was completely omitted bilaterally (Fig. 1B). In the right hand there was a general crowding of carpals; trapezoid was absent and trapezium was hypoplastic. In the left hand trapezoid and scaphoid were missing while trapezium was dysplastic (Fig.1B). Along the ulnar-axis pisiform was not visible. Distal heads of radius and ulna were hypoplastic (Fig. 1C). Case II: This male patient of age 6 originated from a rural area of interior Sindh (Table-I). There was bilateral absence of thumbs and mild shortening of arms (Table-II; Fig. 1D). Case III: The six years school-going male subject belonged to South KhyberPakhtunkhwa (KPK). He was observed to have unilateral aplasia of left thumb (Fig. 1E). Additionally there was mild medial deviation of index finger and shortening of the arm (Table-II). Case IV: The patient was a three years otherwise healthy and jolly baby-girl. She was a product of first-cousin union (F= 0.0625) (Table-I). There was unilateral aplasia of left thumb (Fig. 2B). There was a history of second/third toes syndactyly in a maternal aunt and polydactyly (postaxial type B in hands only) in a fourth degree relative (Fig. 2A). Case V: The seven years male subjects originated from North KPK (Table-I). He had short right arm with reduced zeugopod and limited movements at the elbow joint (Fig. 2C D). There was complete agenesis of right thumb. Additionally there was medial inclination of index finger and clinodactyly of 5th finger. In the left hand the thumb demonstrated minor sign of hypoplasia (Fig. 2C). Case VI: The male subject was 26 years of age. There was unilateral aplasia of left thumb (Fig. 3A. The affected autopod had a reduced palm while the wrist and elbow joints demonstrated limited extension/flexion movements. Additionally there was shortening of the affected arm (Fig. 3A; Table- II). He was engaged in technical job and could manage his occupational duties mainly with the right hand. Radiographic study revealed absent trapezoid and hypoplastic scaphoid. There was fusion of trapezium and capitate and lunate and triquertal (Fig. 3B). There was shortening of radius and ulna and the proximal head of radius was posteriorly dislocated (Fig. 3C). Fifth digits were short and demonstrated only one flexion crease bilaterally. Radiographs of the right hand were unremarkable except crowding of carpals.

DISCUSSION

We describe six independent patients with absent thumbs. According to the classification of thumb hypoplasia revised by Blauth and Schneider- Sickert4 and James et al.5 the phenotypes in all the cases were consistent with hypoplastic thumb type-V". The malformation was bilateral in two individuals (I II) and unilateral in other four (III- VI). Interestingly in the unilateral cases there was high preponderance of involvement of the left hand (n=3/4). Only in one case of unilateral thumb aplasia (i.e. patient V) there was minor hypoplasia of contralateral thumb. Other common observations in the affected autopods were clinodactyly or shortening of 5th digits short and narrow palms and reduced arm lengths. All the patients had normal IQ and there was no involvement of any other organ-systems. Family histories were devoid of thumb aplasia/hypoplasia in all cases. In patient IV however there was occurrences of syndactyly and polydactyly in two different sibships.The phenotypic spectrum of limb reduction defects in the Pakistani patients has not been well- described and only few cases have been reported.910Malik and Jabeen reported a sporadic Pakistani case with thumb aplasia of right hand.11 That patient had additional findings of unilateral zygodactyly of left foot low weight and a lean body. Another male patient a product of consanguineous marriage has been recently reported from Pakistan who had complete absence of thumb and index finger in left hand.8 The subject had additional findings of ulnar deficiency shortening of left arm reduced zeugopod and autopod and severe flexion contracture at the elbow joint. In all of our present cases there was isolated thumb deficiency.Thumb is responsible for proper functioning of hand that is important for independent life activities. Thumb aplasia is usually associated with reduction of hand musculature narrowing of palm and reduction the size of arm/hand which negatively affects functioning of hand and in some cases cause great psychological burden for the child/patient. Thus the parents have responsibility of helping their children in dealing with their feelings of grief responsibility and guilt.12 In our study it was observed that the individuals had adopted the situations accordingly. For instance patient I was well-trained to perform almost all her

house-hold activities. However she had difficulty in carrying heavy articles and fast-grasping of objects. Patients with thumb agenesis develop the habit of grasping objects between the index and long fingers. In the situations with unilateral thumb agenesis the patient remained more dependent on the contralateral normal hand.The molecular etiology of thumb hypoplasia/ aplasia remains less described.5 There is no specific genetic factor known to cause isolated thumb aplasia. However genetic basis of several syndromic form of first digital ray deficiency have been discovered. Holt-Oram syndrome (OMIM-142900) involves absent thumbs along with radial deficiency and cardiac anomalies.12 One form of Holt-Oram syndrome is caused by mutations in TBX5. Fanconi anemia (OMIM-227650) is characterized by radial deficiency in addition to leukemia and symptoms in kidneys and skin and is known to be caused by at least thirteen different genes.1 Similarly Duane- radial ray syndrome (OMIM-607323) is similar to Holt-Oram syndrome with additional symptoms in eyes ears and kidneys and is associated with mutations in SALL4. VACTERAL syndrome which is characterized by absent or hypoplastic thumb along with complications in vertebral renal cardiac and respiratory systems is known to be caused by mutations in TCSK5.12Thumb is a vital digit responsible for proper functioning of hand. For the management of thumb agenesis pollicisation of the index finger is generally performed in which the index finger is placed at the position of thumb. In this case the subject is able to perform normal functions with three fingers and one thumb.13 Majority of the Pakistani subjects with limb deficiencies are less fortunate in finding expert surgical opinion to manage their conditions. In most of the situations the affected individuals belong to low socio-economic background and are unable to bear the expenses of surgical procedures. Even though all of our recruited subjects with thumb aplasia otherwise had normal lives and had adopted to perform their daily activities with the existing four fingers in the involved hands; however pollicisation procedures of the affected hands of these individuals could be highly beneficial for their occupational and personal lives and would remarkably improve their standards of living. Thumb agenesis is uncommon and most of the isolated cases are sporadic and non-familial thus limiting the number of patients who are available for molecular analyses. Therefore collection of such cases is imperative for successful molecular genetics investigations. Recent advances in technology like comparative genomic hybridization SNP arrays and whole-exom analyses could help in the identification of causative mutations in sporadic cases.

ACKNOWLEDGEMENTS

We gratefully acknowledge the participation of the patients in this study. The cooperation of doctors at various medical institutes of Pakistan is also appreciated. This study was supported by the HEC-Pakistan and PSF-Islamabad.

Conflict of interest: The authors have no conflictsof interest.

REFERENCES

1. OMIM. Online Mendelian Inheritance in Man OMIM(R).McKusick-Nathans Institute of Genetic Medicine JohnsHopkins University (Baltimore MD). [accessed Mar. 9 2014]URL: http://omim.org/2. Temtamy SA McKusick VA. The genetics of handmalformations. New York: Alan R. Liss; 1978;44-48 364-392.3. Castriota-Scanderbeg A Dallapiccola B. Hands. In: Castriota-Scanderbeg A Dallapiccola B Edn. Abnormal SkeletalPhenotypes: From Simple Signs to Complex Diagnoses. BerlinHeidelberg: Springer-Verlag; 2005:437-441.4. Blauth W Schneider-Sickert F. Congenital deformities of thehand. An atlas of their surgical treatment. New York: Springer;1981:120-121.5. James MA McCrroll HRJR Manske PR. Characteristics ofpatients with hypoplastic thumbs. J Hand Surg. 1996;21:104-113.6. McGuirk CK Westgate MN Hlmes LB. Limb deficiencies innewborn infants. Pediatrics. 2001;108:E64.7. Assir MZ Waseem T. Spondylocarpotarsal synostosis withhydromyelia mega cisterna magna and pachydermoperiostosis.Clin Dysmorphol. 2012;21(3):144-7. DOI: 10.1097/MCD.0b013e3283543224.8. Malik S Afzal M. Ulnar aplasia dysplastic radius and preaxialoligodactyly: Rare longitudinal limb defect in a sporadic malechild. J Res Med Sci. 2013;18(9):86-89.9. Malik S Afzal M. Congenital terminal transverse deformityof upper limb: clinical and radiological findings in a sporadiccase. J Coll Physicians Surg Pak. 2013;23:219-220. DOI: 03.2013/JCPSP.219220.10. Riaz HF Malik S. Case report of a neonate with congenitaltransverse deficiency of hand. Pak J Med Sci. 2011;27:1177-1180.11. Malik S Jabeen N. Zygodactyly with thumb aplasia: an unusualvariant in a male subject. J Col Phy Surg Pak. 2011;21:710-712.DOI: 11.2011/JCPSP.710712.12. Flatt AE. Our thumbs. BUMC Proc. 2002;15:380-387.13. Tay SC Moran SL Shin AY Cooney WP 3rd. The hypoplasticthumb. J Am Acad Orthop Surg. 2006;14(6):354-366.
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Publication:Pakistan Journal of Medical Sciences
Geographic Code:9PAKI
Date:Jun 30, 2014
Words:2475
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