Embryology, Hand


Article Author:
Jesse Raszewski


Article Editor:
Paramvir Singh


Editors In Chief:
Eric Flake


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Frank Smeeks
Kristina Soman-Faulkner
Trevor Nezwek
Radia Jamil
Patrick Le
Sobhan Daneshfar
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Navid Mahabadi
Steve Bhimji
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
2/19/2019 4:12:33 PM

Introduction

Fetal development occurs in three separate and distinct phases. The first is the predifferentiation period in weeks 1 and 2, the second is the embryonic period that occurs during weeks 3 through 8, and the last is the fetal period from week 9 onward. During the embryonic period, differentiation of the upper limb morphology begins with the upper limb bud around the fifth week. The collection of cells located at the distal ridge of the limb bud, defined as the apical ectodermal ridge, mediates the differentiation and maturation process for the upper extremity. Mesenchymal condensation leads to the formation of cartilaginous analogs of the shoulder, the arm, the forearm, and ultimately the hand. These analogs ossify into bones around week 6 of gestation. The primary centers of ossification begin to form long bones as early as the 12th week. The sequential formation of the cavities in the joints, the condensation of the ligaments, and differentiation of the muscles begins first in the shoulder girdle and proceeds distally to the hand during the 6- to 8-week time frame. After 9 weeks, the bones, joints, ligaments, and muscles undergo further maturation.[1]

Development

Fetal hand morphogenesis, which occurs between 6 and 14 weeks of gestation, can be described in three distinct phases of development, the shape from 6 to 10 weeks, the appearances of creases from 10 to 13 weeks, and creation of ridges from weeks 13 onward. In the first phase during weeks, 6 through 10, the entire external shape of the hand is accomplished in gestation. The first organization of the hand occurs with asymmetry of the hand primordium and development of the slot for the thumb as early as 6 weeks. During weeks 8 through 10, all of the fingers achieve the same spatial plane, and the thumb rotates. This is also when the configuration of the digital and interdigital pads are acquired progressively and become prominent. In the second phase of development, both types of pads begin to regress. The interdigital pads begin to regress around 11 weeks, and the digital pads follow during week 13 onward. Around 10 weeks, the thenar pattern area emerges due to the opposition of the thumb which creates the first appearance of the crease. In the next 2 weeks, the proximal palmar and distal palmar creases become more evident. The last crease to appear is the interphalangeal flexion crease. The appearances of ridges define the third phase. The scanning electron microscope can portray the formation of ridges beginning off the lateral part of the fingertips, which proceeds from a lateral to distal then more of a medial to a proximal position on the end of the phalanx.[2]

Cellular

The formation of digits in the hand occurs at a cellular level. The spaces between each digit form in a distal to proximal direction by two distinct processes of apoptosis and lysosomal enzyme-mediated cell death. In the early phases of cell death, the interdigital mesenchyme expresses high levels of caspase-activated DNases and normal levels of lysosomal DNases. In other words, apoptosis occurs at much higher levels than the enzyme-mediated lysosomal degradation. Apoptosis occurs when different death stimuli, or pro-apoptotic proteins, stimulate the mitochondria within the cells. The mitochondria release cytochrome C, which combines with different factors within the cell to create the “apoptosome.” This leads to the activation of many different caspases that ultimately activate the DNases. The fragmented cells are removed by phagocytosis. During the late phases of cell death, genes encoding superoxide dismutase and catalase are down-regulated. In other words, apoptosis occurs at very low levels, and enzyme-mediated lysosomal degradation occurs at high levels. Reactive oxygen species and cathepsins induce lysosomal-mediated cell death.[3]

Biochemical

There are three axes of development in the hand, and the biochemical role of different factors defines them. Limb growth and differentiation progress in a proximodistal manner for elongation of the limb, anteroposterior manner that defines preaxial and postaxial orientation, and dorsoventral manner which provides the dorsal and palmar orientation. The anteroposterior axis is mediated by the zone of polarizing activity, which secretes the protein Sonic hedgehog (Shh). This establishes the radial and ulnar sides of the limb and is the first axis to develop. The dorsoventral axis is not as well understood. It produces a protein called the wingless-type mouse mammary tumor virus integration site family member 7a (Wnt-7a). This protein induces transcription of the factor LIM homeobox transcription factor (Lmx1), which is required for dorsalization of the limb bud. As this is occurring, a negative feedback loop occurs on the ventral side. The transcription factor engrailed-1 (En-1) inhibits the Wnt-7a expression. This establishes the palmar and dorsal aspects of the hand. The apical epidermal ridge mediates the proximodistal axis. This thickened ridge secretes several fibroblast growth factors that differentiate the limb bud. This promotes elongation of the limb and is the last axis to develop.[4]

Molecular

At the molecular level, protein factors, such as ligands, receptors and transcription factors, play a critical role in the development of the limb. Sonic hedgehog (Shh) and fibroblast growth factors are specific ligands and serve important roles in cell signaling. These ligand factors induce differentiation and proliferation of neighboring cell populations within the nascent limb. These ligands stimulate signal transduction to cause structural and functional changes in cell behavior.This causes transcription factors to travel into the nucleus of the cell and create new DNA.[5] Both of these factors lead to the expression of new genes. Research continues to clarify the partially understood mechanisms of the molecular biology of the developing hand.

Function

The hand consists of tendons, ligaments, and bones. There are 27 bones total, consisting of 14 in the phalanges of the fingers, five metacarpal bones, and eight carpal bones. The bones in the hand are positioned and connected with ligaments. The tendons are what insert the muscle into the bones and are divided into the flexor components and the extensor components. The flexor tendons are located on the palmar side of the hand, and the extensor tendons are located on the dorsal aspect of the hand. The motor and sensory functions of the hand are mediated by the median, ulnar and radial nerves. The median nerve innervates the thenar muscles, index and middle finger lumbrical muscles, the ulnar nerve innervates all of the rest of the intrinsic muscles in the hand. Malfunction of any of these components of the hand may lead to injury or wear that ultimately leads to decreased functionality and disability.[6]

Mechanism

The nerves acting on the muscles regulate the function and mechanisms of the hand. Below are the muscles, nerves, and the mechanisms of action produced by the combination.

Thenar Muscles

Opponens pollicis

  • Mechanism: Opposition of the thumb
  • Nerve: Recurrent branch of median nerve (C8, T1)

Abductor pollicis brevis

  • Mechanism: Abduction of the thumb
  • Nerve: Recurrent branch of median nerve (C8, T1)

Flexor pollicis brevis

  • Mechanism: Flexion of the thumb
  • Nerve: Recurrent branch of median nerve (C8, T1)

Adductor Compartment

Adductor pollicis

  • Mechanism: Adduction of the thumb
  • Nerve: Deep branch of ulnar nerve (C8, T1)

Hypothenar Muscles

Abductor digiti minimi

  • Mechanism: Abduction of the little finger
  • Nerve: Deep branch of ulnar nerve (C8, T1)

Flexor digiti minimi brevis

  • Mechanism: Flexion of the little finger
  • Nerve: Deep branch of ulnar nerve (C8, T1)

Opponens digiti minimi

  • Mechanism: Opposition of the little finger
  • Nerve: Deep branch of ulnar nerve (C8, T1)

Short Muscles

Lumbricals

  • Mechanism: Flexion of the metacarpophalangeal joints with the extension of the interphalangeal joints
  • Nerve: Median nerve (C8, T1) for the lateral two lumbricals, deep branch of ulnar nerve (C8, T1) for the medial two lumbricals

Dorsal interossei

  • Mechanism: Abduction of the second, third, and fourth finger
  • Nerve: Deep branch of ulnar nerve (C8, T1)

Palmar interossei

  • Mechanism: Adduction of the second, third, and fourth finger
  • Nerve: Deep branch of ulnar nerve (C8, T1)[7]

Testing

Fluorescent cell markers have been used to construct a map of the apical ectodermal ridge. The cells located in the posterior region give rise to the ectodermal ridge, and the anterior region cells leave the ridge as the bud grows distally. Retinoic acid may be used to alter this normal progression of the apical ridge to create a mirror-image duplication. Labeling experiments have also demonstrated that the cells from the underlying mesenchyme do not keep in line with the ridge as it expands in the anterior direction.[8] Future research devoted to the epithelium is fundamental because of the crucial role it plays in the development of organs.

Pathophysiology

During the embryonic period in gestation, limb territories are first determined in the right positions along the cephalocaudal axis. The limb bud grows out from the body as a mesenchymal cell mass covered by ectoderm. The identity, position and cell masses depend on the expression of Hox genes.[9]

The first category of limb malformations is a failure of formation, which is arrestment of development of a particular portion of the limb. Transverse deficiencies include all congenital amputations, such as shoulder, arm, forearm, carpals, metacarpals, and phalangeal clinical entities. Longitudinal deficiencies include all the skeletal limb deficiencies not included in the transverse, such as phocomelias. These may range from partial to complete absence. The second category of limb malformation is a failure of differentiation, which is defined as the basic unit of the limb has developed, but its final form is incompletely developed. An example of this is syndactyly or incomplete separation of the adjacent digits. The third category is duplication, which results from an insult to the apical ectodermal ridge during development. An example of this is polydactyly. The fourth category is known as overgrowth, which is a nonhereditary congenital enlargement. This commonly presents in the digits. The fifth category is denoted as hypoplasia or undergrowth, where there is incomplete growth during the fetal period. The last category is included but is considered a separate entity. It is congenital constriction of a limb due to bands, which leads to subsequent loss of the part.[1]

Clinical Significance

The intimate relationship between the structure and the function in the hand poses a hindrance when approaching surgical correction in anomalies. During surgical planning, functional restoration should overrule structural corrections. The goals are to improve function, maintain cosmesis, and limit complications that could impair the patient in the long term. The surgeon needs to balance functional, cosmetic and cultural goals that align with the patient and parents and the surgical technique that is indicated.[10] This leads to patient satisfaction and improved outcomes.


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Embryology, Hand - Questions

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During the routine newborn exam, a patient presents with atrophied thenar muscles and limited mobility at the knuckle of his right hand. Imaging is likely to reveal a skeletal abnormality of that developed at which joint during which of the following stages of development?



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Which of the following is the last morphological feature of the hand to become prominent in the development of the upper extremity?



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Which of the following is not one of the three different axes of development in the hand?



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The formation of the digits occurs at a cellular level during the embryogenesis of the hand. The spaces between each finger are formed by the process of apoptosis. Which of the following does the mitochondria release that binds several factors to make the "apoptosome" during the process of apoptosis to create the interdigital spaces?



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Which of the following is primarily instrumental in proximal-distal upper limb development?



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According to Manske modification of the Blauth classification for thumb hypoplasia, which type warrants treatment with opponensplasty?



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Embryology, Hand - References

References

Van Heest AE, Congenital disorders of the hand and upper extremity. Pediatric clinics of North America. 1996 Oct;     [PubMed]
Lacroix B,Wolff-Quenot MJ,Haffen K, Early human hand morphology: an estimation of fetal age. Early human development. 1984 Feb;     [PubMed]
Al-Qattan MM, Formation of normal interdigital web spaces in the hand revisited: implications for the pathogenesis of syndactyly in humans and experimental animals. The Journal of hand surgery, European volume. 2014 Jun;     [PubMed]
Sammer DM,Chung KC, Congenital hand differences: embryology and classification. Hand clinics. 2009 May;     [PubMed]
Cole P,Kaufman Y,Hatef DA,Hollier LH Jr, Embryology of the hand and upper extremity. The Journal of craniofacial surgery. 2009 Jul;     [PubMed]
Leow MQH,Lim RQR,Tay SC, Clinical Assessment and Diagnostics of Patients With Hand Disorders: A Case Study Approach. Orthopedic nursing. 2017 May/Jun;     [PubMed]
Raszewski JA,Varacallo M, Anatomy, Shoulder and Upper Limb, Hand Compartments 2018 Jan;     [PubMed]
Wolpert L, Pattern formation in epithelial development: the vertebrate limb and feather bud spacing. Philosophical transactions of the Royal Society of London. Series B, Biological sciences. 1998 Jun 29;     [PubMed]
Koussoulakos S, Vertebrate limb development: from Harrison's limb disk transplantations to targeted disruption of Hox genes. Anatomy and embryology. 2004 Dec;     [PubMed]
Little KJ,Cornwall R, Congenital Anomalies of the Hand--Principles of Management. The Orthopedic clinics of North America. 2016 Jan;     [PubMed]

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