自然経過
その他，軟骨無形成症患者の自然経過と適切な介入法に関して，詳細な要約が発表されている[Trotter et al 2005，Pauli 2010]．
軟骨無形成症患者は，四肢の肢根型短縮が原因の低身長，前額部の突出と顔面中央部の下顎後退を呈する特徴的な顔貌，極度の腰椎前弯，肘の伸張および回転制限，内反膝，短指症と三尖手を有する．膝，股関節その他の関節は，関節可動域が過剰である場合が多い．
軟骨無形成症の成人男性の平均身長は131±5．6 cmであり，女性は124±5．9 cmである．軟骨無形成症では肥満が大きな問題となる[Hecht et al 1988]．過剰な体重増加が小児初期に明らかになる．成人の場合，肥満が腰部脊柱管狭窄症関連の罹病率を悪化させかねず，非特異的関節障害が生じやすくなり，心血管合併症による早期死亡に至ることもある[Hecht et al 1988]．
乳児期では軽度から中等度の筋緊張低下が多く，運動面の発達段階の獲得が遅滞したり，稀な異常パターンを呈することもある[Fowler et al 1997，Ireland et al 2010]．乳児は筋緊張低下と大きな頭部のため，自らの頭部を支えることが困難である．
水頭症やその他の中枢神経系合併症が生じない限り，知能は正常である．
軟骨無形成症患者では真性巨脳症が起こり，軟骨無形成症の大多数の患児に大頭症を認める[Horton et al 1978]．治療を要する水頭症が起こるのはおそらく5％未満[Pauli 2010]であるが，頭蓋内静脈圧の亢進が頸静脈孔の狭窄が原因で生じる可能性がある[Pierre-Kahn et al 1980，Steinbok et al 1989]．
軟骨無形成症の乳児の中には，頭頸接合部関連の合併症により生後1年以内に死亡する者もいる．地域住民調査研究では，これが原因の死亡リスクはきわめて高く，7．5％であることが示された[Hecht et al 1987]．このリスクは，呼吸制御中枢の損傷に関連する中枢型無呼吸に続発すると考えられ[Nelson et al 1988，Pauli et al 1995]，軟骨無形成症の乳児全員に対する包括的評価[Trotter et al 2005]や神経外科的介入を選択的に行うことにより，リスクの低下が可能である．1件の研究[Pauli et al 1995]では，頭頸接合部に対する外科的減圧術を施行した患児全員で，神経機能の顕著な改善を認めた．手術後，最長20年間に渡って測定したQOL指標は，小児期に手術が適応にならなかった者のQOL指標と同等であった [Ho et al 2004]．
年長児と成人に多く認める閉塞性睡眠時無呼吸は[Waters et al 1995， Sisk et al 1999]，気道を縮小させる顔面中央部の下顎後退[Stokes et al 1983， Waters et al 1995]とリンパ組織環の肥大と，おそらく気道筋系の異常な神経支配[Tasker et al 1998]との合併症により生じる．
中耳機能障害が頻繁に生じ[Berkowitz et al 1991]，治療が不適切な場合には言語発達に影響して重度の難聴となりかねない．
軟骨無形成症患者では下肢の弯曲が極めて多い[Kopits 1988a]．未治療の成人の90％以上には，ある程度の弯曲を認める[Kopits 1988a]．「弯曲」は実際，外弯，脛骨内捻転，膝の動的不安定の組み合わせから生じる複合的奇形である[Inan et al 2006]．
軟骨無形成症の乳児の90～95％に胸腰結合部の後弯を認める[Kopitz 1988b，Pauli et al 1997]．約10％は自然回復せず，重篤な神経的後遺症に至りやすい[Kopits 1988b]．予防手段[Pauli et al 1997]を講じることにより，外科的介入の必要性を低下できることがある[Ain & Browne 2004，Ain & Shirley 2004]．
成人期で最も多い医学的愁訴はL1-L4の脊柱管狭窄症による症状である[Kahanovitz et al 1982]．症状は，可逆的な運動誘発性間欠性跛行から重度で不可逆的な下肢機能の異常や失禁に及ぶ[Pyeritz et al 1987]．
軟骨無形成症の成人での死亡率の高さが報告されている[Hecht et al 1987，Wynn et al 2007]．Wynn et al 2007では，25～35歳の心疾患関連死亡率が10倍となっており，総じて寿命は約10年短縮しているようである．
軟骨無形成症のホモ接合体．FGFR3遺伝子の1138ヌクレオチドの変異アレルが2つ存在する軟骨無形成症のホモ接合体では，軟骨無形成症のX線所見とは質の異なる変化を伴う重度障害をきたす．狭隘な胸郭と頸延髄狭窄による神経障害から呼吸不全が生じることが原因で，早期死亡に至る[Hall 1988]．
遺伝子型と臨床型の関連
軟骨無形成症のほぼ全症例が同一のアミノ酸置換に続発して発症しているため，一次変異に関連した遺伝子型と臨床型の相関関係はないと考えられる．
浸透率
浸透度は100％であり，軟骨無形成症を発症させるFGFR3遺伝子変異のコピーを1つ持つ者はすべて軟骨無形成症の臨床症状を呈する．
表現促進現象
表現促進現象は観察されない．
病名
歴史的に見ると，当初，軟骨無形成症という用語は，四肢が短い低身長症患者すべてに用いられていた．軟骨無形成症はその他の低身長症と比べて発症頻度が多く，「小人（dwarf）」という用語はこれまで軟骨無形成症患者に対して用いられることが極めて多かった．過去40年間に診断基準が作成され，軟骨無形成症は，外見上同様の病態を呈する他の疾患と鑑別できるようになった．
頻度
軟骨無形成症は，遺伝性の不均衡な低身長を有する最も一般的な病態である．最も正確な発症率の推定値は，生児出産の26，000～28，000人のうち1人である[Oberklaid et al 1979，Orioli et al 1995]．
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軟骨無形成症 (Achondroplasia)
Gene Review著者: Richard M Pauli, MD, PhD
日本語訳者: 窪田美穂（ボランティア翻訳者），澤井英明（兵庫医科大学）
Gene Review 最終更新日: 2012.2.16. 日本語訳最終更新日: 2012.4.16.
Clinical Description
Other, extensive summaries of the natural history and appropriate interventions in individuals with achondroplasia have been published [Trotter et al 2005, Pauli 2010].
Individuals with achondroplasia have short stature caused by rhizomelic shortening of the limbs, characteristic facies with frontal bossing and midfacial retrusion, exaggerated lumbar lordosis, limitation of elbow extension and rotation, genu varum, brachydactyly, and trident appearance of the hands. Excess mobility of the knees, hips, and most other joints is common.
Average adult height for men with achondroplasia is 131±5.6 cm; for women, 124±5.9 cm. Obesity is a major problem in achondroplasia [Hecht et al 1988]. Excessive weight gain is manifest in early childhood. In adults, obesity can aggravate the morbidity associated with lumbar stenosis and contribute to nonspecific joint problems and possibly to early mortality from cardiovascular complications [Hecht et al 1988].
In infancy, mild to moderate hypotonia is typical, and acquisition of developmental motor milestones is delayed and also shows unusual, aberrant patterns [Fowler et al 1997, Ireland et al 2010]. Infants have difficulty in supporting their heads because of both hypotonia and large head size.
Intelligence is normal unless hydrocephalus or other central nervous system complications occur.
True megalencephaly occurs in individuals with achondroplasia and most children with achondroplasia are macrocephalic [Horton et al 1978]. Hydrocephalus requiring treatment, which probably occurs in 5% or fewer [Pauli 2010], may be caused by increased intracranial venous pressure because of stenosis of the jugular foramina [Pierre-Kahn et al 1980, Steinbok et al 1989].
Some infants with achondroplasia die in the first year of life from complications related to the craniocervical junction; population-based studies suggest that this excess risk of death may be as high as 7.5% [Hecht et al 1987]. The risk appears to be secondary to central apnea associated with damage to respiratory control centers [Nelson et al 1988, Pauli et al 1995], and can be minimized by comprehensive evaluation of every infant with achondroplasia [Trotter et al 2005] and selective neurosurgical intervention. In one study [Pauli et al 1995] all children undergoing surgical decompression of the craniocervical junction showed marked improvement of neurologic function. Quality of life indices determined up to 20 years after such surgery were comparable to quality of life indices in those for whom surgery was not indicated in childhood [Ho et al 2004].
Obstructive sleep apnea, common in both older children and adults [Waters et al 1995, Sisk et al 1999], arises because of a combination of midfacial retrusion resulting in smaller airway size [Stokes et al 1983, Waters et al 1995], hypertrophy of the lymphatic ring and, perhaps, abnormal innervation of the airway musculature [Tasker et al 1998].
Middle ear dysfunction is frequently a problem [Berkowitz et al 1991], which, if inadequately treated, can result in hearing loss of sufficient severity to interfere with language development.
Bowing of the lower legs is exceedingly common in those with achondroplasia [Kopits 1988a]. More than 90% of untreated adults have some degree of bowing [Kopits 1988a]. ‘Bowing’ is actually a complex deformity arising from a combination of lateral bowing, internal tibial torsion and dynamic instability of the knee [Inan et al 2006].
Kyphosis at the thoracolumbar junction is present in 90%-95% of infants with achondroplasia [Kopitz 1988b, Pauli et al 1997]. In about 10% it does not spontaneously resolve and can result in serious neurologic sequelae [Kopits 1988b]. Preventive strategies [Pauli et al 1997] may reduce the need for surgical intervention [Ain & Browne 2004, Ain & Shirley 2004].
The most common medical complaint in adulthood is symptomatic spinal stenosis involving L1-L4 [Kahanovitz et al 1982]. Symptoms range from intermittent, reversible, exercise-induced claudication to severe, irreversible abnormalities of leg function and of continence [Pyeritz et al 1987].
Increased mortality in adults with achondroplasia has been reported [Hecht et al 1987, Wynn et al 2007]. In the latter study, there was a tenfold increase in heart disease-related mortality between ages 25 and 35 and, overall, life expectancy appeared to be decreased by about ten years.
Homozygous achondroplasia, caused by the presence of two mutant alleles at nucleotide 1138 of FGFR3, is a severe disorder with radiologic changes qualitatively different from those of achondroplasia. Early death results from respiratory insufficiency because of the small thoracic cage and neurologic deficit from cervicomedullary stenosis [Hall 1988].
Genotype-Phenotype Correlations
Because nearly all instances of achondroplasia arise secondary to identical amino acid substitutions, genotype-phenotype correlation related to the primary mutation is not possible.
Penetrance
Penetrance is 100%, meaning that all individuals who have a single copy of one of the FGFR3 mutations giving rise to achondroplasia have the clinical manifestations of the disorder.
Anticipation
Anticipation is not observed.
Nomenclature
Historically, the term achondroplasia was initially used to describe all individuals with short-limbed dwarfing disorders. Because achondroplasia is so common compared to other small stature processes, the term ‘dwarf’ was previously used most often to refer to an individual with achondroplasia. Over the past 40 years diagnostic criteria have been available to distinguish true achondroplasia from other, superficially similar processes.
Prevalence
Achondroplasia is the most common form of inherited disproportionate short stature. Best estimates are that it occurs in 1:26,000-1:28,000 live births [Oberklaid et al 1979, Orioli et al 1995].
Achondroplasia
University of Wisconsin – Madison
Madison, Wisconsin
Initial Posting: October 12, 1998; Last Update: February 16, 2012.