Editing Kocher–Debre–Semelaigne syndrome

{{short description|Hypothyroidism in infancy or childhood}}
{{Infobox medical condition (new)
| name            = Kocher–Debré–Semelaigne syndrome
| synonyms        = Debré–Semelaigne syndrome, cretinism-muscular hypertrophy, hypothyroidism-large muscle syndrome, hypothyreotic muscular hypertrophy in children, infantile myxoedema-muscular hypertrophy, myopathy-myxoedema syndrome, myxoedema-muscular hypertrophy syndrome, myxoedema-myotonic dystrophy syndrome, muscular pseudohypertrophy-hypothyroidism syndrome
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'''Kocher–Debré–Semelaigne syndrome''' ('''KDSS''') is [[hypothyroidism]] in infancy or childhood characterised by lower extremity or generalized muscular hypertrophy ([[Pseudoathletic appearance|Herculean appearance]]<ref name=":0">{{cite book |last1=Sainani |first1=JP |title=Clinical Cases & Pearls in Medicine |date=2015 |publisher=JP Medical Ltd. |isbn=9789351526469 |page=333}}</ref>), [[myxoedema]], [[short stature]], and [[cognitive impairment]].<ref>{{cite book|last1=Millichap|first1=J. Gordon|title=Neurological syndromes : a clinical guide to symptoms and diagnosis|date=2013|publisher=Springer New York|location=New York, NY|isbn=9781461477860|page=121}}</ref>

The syndrome is named after [[Emil Theodor Kocher]], [[Robert Debré]] and Georges Semelaigne. Also known as Debré–Semelaigne syndrome or cretinism-muscular hypertrophy, hypothyroid myopathy, hypothyroidism-large muscle syndrome, hypothyreotic muscular hypertrophy in children, infantile myxoedema-muscular hypertrophy, myopathy-myxoedema syndrome, myxoedema-muscular hypertrophy syndrome, myxoedema-myotonic dystrophy syndrome.

The adult-onset form of this syndrome is [[Hoffmann syndrome]].<ref>{{cite book |last1=Bhansali |first1=Anil |title=Clinical Rounds in Endocrinology: Volume II - Pediatric Endocrinology |last2=Aggarwal |first2=Anuradha |date=2016 |publisher=Springer |isbn=9788132228158 |page=81}}</ref> Some sources claim that two of the differentiating symptoms between KDSS and Hoffmann syndrome is that Hoffmann syndrome lacks painful spasms and pseudomyotonia;<ref name=":0" /><ref>{{Cite journal |last1=Agrawal |first1=Sanwar |last2=Thakur |first2=Prashant |date=2010-12-16 |title=Kocher–Debré–Semelaigne syndrome |journal=BMJ Case Reports |volume=2010 |pages=bcr0420102877 |doi=10.1136/bcr.04.2010.2877 |issn=1757-790X |pmc=3029797 |pmid=22802324}}</ref> however, this claim is in conflict with other sources that list these symptoms as also being present in Hoffmann syndrome.<ref>{{Cite journal |last1=Vasconcellos |first1=Luiz Felipe Rocha |last2=Peixoto |first2=Maria Claudia |last3=de Oliveira |first3=Tatiana Nunes |last4=Penque |first4=Glória |last5=Leite |first5=Ana Claudia Celestino |date=September 2003 |title=Hoffman's syndrome: pseudohypertrophic myopathy as initial manifestation of hypothyroidism. Case report |journal=Arquivos de Neuro-Psiquiatria |volume=61 |issue=3B |pages=851–854 |doi=10.1590/s0004-282x2003000500027 |issn=0004-282X |pmid=14595495|doi-access=free }}</ref><ref name=":1">{{Cite journal |last1=Mangaraj |first1=Swayamsidha |last2=Sethy |first2=Ganeswar |date=2014 |title=Hoffman's syndrome – A rare facet of hypothyroid myopathy |journal=Journal of Neurosciences in Rural Practice |volume=5 |issue=4 |pages=447–448 |doi=10.4103/0976-3147.140025 |issn=0976-3147 |pmc=4173264 |pmid=25288869 |doi-access=free }}</ref><ref>{{Cite journal |last1=Udayakumar |first1=N. |last2=Rameshkumar |first2=A. C. |last3=Srinivasan |first3=A. V. |date=2005 |title=Hoffmann syndrome: presentation in hypothyroidism |url=https://pubmed.ncbi.nlm.nih.gov/16388183/ |journal=Journal of Postgraduate Medicine |volume=51 |issue=4 |pages=332–333 |issn=0022-3859 |pmid=16388183}}</ref><ref>{{Cite journal |last1=Qureshi |first1=Waseem |last2=Hassan |first2=Ghulam |last3=Khan |first3=Ghulam Qadir |last4=Kadri |first4=Syed Manzoor |last5=Kak |first5=Manish |last6=Ahmad |first6=Manzoor |last7=Tak |first7=Shahid |last8=Kundal |first8=Darshan Lal |last9=Hussain |first9=Showkat |last10=Rather |first10=Abdul Rashid |last11=Masoodi |first11=Ibrahim |last12=Sikander |first12=Sabia |date=2005-07-20 |title=Hoffmann's syndrome: a case report |journal=GMS German Medical Science |volume=3 |pages=Doc05 |issn=1612-3174 |pmc=2703243 |pmid=19675722}}</ref>

== Presentation ==
The age at which a child presents with KDSS may vary from new born to as late as 11 years of age.<ref name=":2" /> This disease is very rare as only less than 10% of children with hypothyroid myopathy develops this condition.{{Citation needed|date=July 2023}} Along with features of [[hypothyroidism]] (such as lethargy, slow heart rate, cold intolerance, dry skin, and hoarse voice) the main additional feature is muscle hypertrophy. It can happen in any muscle of the limbs, but commonly affects the calf muscles, giving the typical Herculean appearance.<ref name=":2">{{Cite journal|last1=Tullu|first1=Milind S.|last2=Udgirkar|first2=Vardhaman S.|last3=Muranjan|first3=Mamta N.|last4=Sathe|first4=Shefali A.|last5=Kamat|first5=Jaishree R.|date=2003-08-01|title=Kocher-Debre-Semelaigne syndrome: Hypothyroidism with muscle pseudohypertrophy|url=https://doi.org/10.1007/BF02724260|journal=The Indian Journal of Pediatrics|language=en|volume=70|issue=8|pages=671–673|doi=10.1007/BF02724260|pmid=14510090 |s2cid=40709054 |issn=0973-7693}}</ref>

Other features are pseudo[[myotonia]], [[myokymia]], slow tendon reflex, slowed muscle contractions and relaxations, muscle stiffness, proximal muscle weakness and myopathy. The severity of these symptoms are determined by the period of hypothyroidism and the degree of deficiency of thyroid hormones.<ref>{{Cite journal|last1=Klein|first1=Irwin|last2=Mantell|first2=Paul|last3=Parker|first3=Mitchell|last4=Levey|first4=Gerald S.|date=May 1980|title=Resolution of abnormal muscle enzyme studies in hypothyroidism|journal=The American Journal of the Medical Sciences|language=en|volume=279|issue=3|pages=159–162|doi=10.1097/00000441-198005000-00004|pmid=7424961|s2cid=11587035}}</ref> It may also include [[macroglossia]].<ref>{{Cite journal |last1=Shaw |first1=Chandan |last2=Shaw |first2=Prachi |date=2012 |title=Kocher-Debre-Semelaigne Syndrome: Hypothyroid Muscular Pseudohypertrophy—A Rare Report of Two Cases |journal=Case Reports in Endocrinology |volume=2012 |pages=153143 |doi=10.1155/2012/153143 |issn=2090-6501 |pmc=3420572 |pmid=22934196 |doi-access=free }}</ref>

EMG is either normal or may show myopathic low amplitude and short duration motor unit action potentials (MUAPS).<ref>{{Cite journal|last1=Rajvanshi|first1=Satyam|last2=Rai|first2=GopalK|last3=Philip|first3=Rajeev|last4=Gupta|first4=KK|date=2012|title=Kocher-Debre-Semelaigne syndrome|journal=Thyroid Research and Practice|volume=9|issue=2|pages=53|doi=10.4103/0973-0354.96047|issn=0973-0354 |doi-access=free }}</ref> The enzymes creatine kinase is elevated usually.

== Pathophysiology ==
The assumed cause of muscle hypertrophy in KDSS is an abnormal metabolism of carbohydrates leading to increased glycogen accumulation and increased [[mucopolysaccharide]] deposits in the muscles.<ref>{{Cite journal|last1=Panat|first1=Sunil R.|last2=Jha|first2=Prakash Chandra|last3=Chinnannavar|first3=Sangamesh N.|last4=Chakarvarty|first4=Ankkita|last5=Aggarwal|first5=Ashish|date=March 2013|title=Kocher Debre Semelaigne Syndrome: A Rare Case Report with Orofacial Manifestations|journal=Oman Medical Journal|volume=28|issue=2|pages=128–130|doi=10.5001/omj.2013.33|issn=1999-768X|pmc=3628204|pmid=23599883}}</ref> Yet another speculation is an excess intra cellular calcium due to ineffective reuptake into the sarcoplasmic reticulum, which causes a sustained contraction and thereby hypertrophy.<ref>{{Cite journal|last=Pourmand|first=Rahman|title=Metabolic Myopathies|date=February 2000|journal=Neurologic Clinics|volume=18|issue=1|pages=1–13|doi=10.1016/s0733-8619(05)70176-6|pmid=10658166|issn=0733-8619}}</ref>

In hypothyroidism the fast twitch muscle fiber is converted to slow twitch fiber, causing the slower reflex or hung up reflex. This may occur as a result of reduction in muscle mitochondrial oxidative capacity and beta-adrenergic receptors, as well as the induction of an insulin-resistant state, due to decrease in thyroid hormones.<ref>{{Cite journal|last1=Benvenga|first1=Salvatore|last2=Toscano|first2=Antonio|last3=Rodolico|first3=Carmelo|last4=Vita|first4=Giuseppe|last5=Trimarchi|first5=Francesco|date=August 2001|title=Endocrine Evaluation for Muscle Pain|journal=Journal of the Royal Society of Medicine|volume=94|issue=8|pages=405–407|doi=10.1177/014107680109400810|pmid=11461987|pmc=1281637|issn=0141-0768|doi-access=free}}</ref>

The causes for muscle weakness is said to be decrease in muscle [[carnitine]], decreased muscle oxidation, expression of a slower [[ATPase]] in myosin chain and decreased transport across the cell membrane.<ref>{{Cite journal|last1=Horak|first1=Holli A.|last2=Pourmand|first2=Rahman|title=Endocrine Myopathies|date=February 2000|journal=Neurologic Clinics|volume=18|issue=1|pages=203–213|doi=10.1016/s0733-8619(05)70186-9|pmid=10658176|issn=0733-8619}}</ref><ref>{{Cite journal|last1=Sinclair|first1=Christopher|last2=Gilchrist|first2=James M.|last3=Hennessey|first3=James V.|last4=Kandula|first4=Manju|date=2005|title=Muscle carnitine in hypo- and hyperthyroidism|journal=Muscle & Nerve|volume=32|issue=3|pages=357–359|doi=10.1002/mus.20336|pmid=15803480|s2cid=41839983 |issn=0148-639X}}</ref>

The rigidity associated with congenital hypothyroidism may be due to abnormal development of basal ganglia.<ref>{{Cite book|last=Barrett, Kim E.|title=Ganong's review of medical physiology|others=Barman, Susan M.,, Brooks, Heddwen L.,, Yuan, Jason X.-J., 1963-, Preceded by: Ganong, William F.|isbn=9781260122404|edition=Twenty-sixth|location=[New York]|pages=848|oclc=1076268769|date=2019-01-29}}</ref>

==Diagnosis==
{{Empty section|date=August 2020}}

== Differential diagnoses ==
Diseases known to have a [[pseudoathletic appearance]] of the calves ([[Muscle hypertrophy|hypertrophy]] or [[pseudohypertrophy]]), including exercise intolerance and/or muscle weakness:

* [[Hoffmann syndrome]] (adult-onset hypothyroid myopathy),
* [[Glycogen storage disease]] (GSD-V, & late-onset GSD-II),<ref>{{Cite journal |last1=Rodríguez-Gómez |first1=I. |last2=Santalla |first2=A. |last3=Díez-Bermejo |first3=J. |last4=Munguía-Izquierdo |first4=D. |last5=Alegre |first5=L. M. |last6=Nogales-Gadea |first6=G. |last7=Arenas |first7=J. |last8=Martín |first8=M. A. |last9=Lucía |first9=A. |last10=Ara |first10=I. |date=November 2018 |title=Non-osteogenic muscle hypertrophy in children with McArdle disease |url=https://pubmed.ncbi.nlm.nih.gov/29594644/ |journal=Journal of Inherited Metabolic Disease |volume=41 |issue=6 |pages=1037–1042 |doi=10.1007/s10545-018-0170-7 |issn=1573-2665 |pmid=29594644|hdl=10578/19657 |s2cid=4394513 |hdl-access=free }}</ref><ref>{{Cite journal |last1=Menon |first1=M. Suraj |last2=Roopch |first2=P. Sreedharan |last3=Kabeer |first3=K. Abdulkhayar |last4=Shaji |first4=C. Velayudhan |date=July 2016 |title=Calf Muscle Hypertrophy in Late Onset Pompe's Disease |url=https://journals.lww.com/armh/Fulltext/2016/04020/Calf_Muscle_Hypertrophy_in_Late_Onset_Pompe_s.22.aspx |journal=Archives of Medicine and Health Sciences |language=en-US |volume=4 |issue=2 |pages=251 |doi=10.4103/2321-4848.196188 |s2cid=58424073 |issn=2321-4848|doi-access=free }}</ref>
* [[Channelopathy|Non-dystrophic myotonias]] and pseudo[[myotonia]]s (such as [[Myotonia congenita]] and [[Brody myopathy|Brody disease]]),<ref>{{Cite journal |last1=Stunnenberg |first1=Bas C. |last2=LoRusso |first2=Samantha |last3=Arnold |first3=W. David |last4=Barohn |first4=Richard J. |last5=Cannon |first5=Stephen C. |last6=Fontaine |first6=Bertrand |last7=Griggs |first7=Robert C. |last8=Hanna |first8=Michael G. |last9=Matthews |first9=Emma |last10=Meola |first10=Giovanni |last11=Sansone |first11=Valeria A. |last12=Trivedi |first12=Jaya R. |last13=van Engelen |first13=Baziel G.M. |last14=Vicart |first14=Savine |last15=Statland |first15=Jeffrey M. |date=October 2020 |title=Guidelines on clinical presentation and management of nondystrophic myotonias |journal=Muscle & Nerve |volume=62 |issue=4 |pages=430–444 |doi=10.1002/mus.26887 |issn=0148-639X |pmc=8117169 |pmid=32270509}}</ref>
* [[Limb–girdle muscular dystrophy|Limb-girdle muscular dystrophy]],<ref>{{Cite journal |last=de Visser |first=Marianne |date=2020-12-01 |title=Late-onset myopathies: clinical features and diagnosis |journal=Acta Myologica |volume=39 |issue=4 |pages=235–244 |doi=10.36185/2532-1900-027 |issn=1128-2460 |pmc=7783434 |pmid=33458579}}</ref>
* [[Duchenne muscular dystrophy|Duchenne]] and [[Becker muscular dystrophy]]
* Focal [[myositis]],
* [[Sarcoid granuloma]]s, and
* [[Amyloid]] deposits in muscles<ref name=":1" />

Thyroid metabolism can be disrupted secondary to a primary disease. A common [[comorbidity]] of the [[metabolic myopathy]] McArdle disease (Glycogen storage disease type V) is hypothyroidism.<ref>{{Cite journal |last1=Lucia |first1=Alejandro |last2=Martinuzzi |first2=Andrea |last3=Nogales-Gadea |first3=Gisela |last4=Quinlivan |first4=Ros |last5=Reason |first5=Stacey |last6=International Association for Muscle Glycogen Storage Disease study group |date=December 2021 |title=Clinical practice guidelines for glycogen storage disease V & VII (McArdle disease and Tarui disease) from an international study group |journal=Neuromuscular Disorders |volume=31 |issue=12 |pages=1296–1310 |doi=10.1016/j.nmd.2021.10.006 |issn=1873-2364 |pmid=34848128|s2cid=240123241 |doi-access=free }}</ref><ref>{{Cite journal |last1=Scalco |first1=Renata S. |last2=Lucia |first2=Alejandro |last3=Santalla |first3=Alfredo |last4=Martinuzzi |first4=Andrea |last5=Vavla |first5=Marinela |last6=Reni |first6=Gianluigi |last7=Toscano |first7=Antonio |last8=Musumeci |first8=Olimpia |last9=Voermans |first9=Nicol C. |last10=Kouwenberg |first10=Carlyn V. |last11=Laforêt |first11=Pascal |last12=San-Millán |first12=Beatriz |last13=Vieitez |first13=Irene |last14=Siciliano |first14=Gabriele |last15=Kühnle |first15=Enrico |date=2020-11-24 |title=Data from the European registry for patients with McArdle disease and other muscle glycogenoses (EUROMAC) |journal=Orphanet Journal of Rare Diseases |volume=15 |issue=1 |pages=330 |doi=10.1186/s13023-020-01562-x |issn=1750-1172 |pmc=7687836 |pmid=33234167 |doi-access=free }}</ref> It is also a comorbidity of late-onset Pompe disease (Glycogen storage disease type II).<ref>{{Cite journal |last1=Schneider |first1=Joseph |last2=Burmeister |first2=Lynn A. |last3=Rudser |first3=Kyle |last4=Whitley |first4=Chester B. |last5=Jarnes Utz |first5=Jeanine |date=2016-07-01 |title=Hypothyroidism in late-onset Pompe disease |journal=Molecular Genetics and Metabolism Reports |volume=8 |pages=24–27 |doi=10.1016/j.ymgmr.2016.06.002 |issn=2214-4269 |pmc=4932620 |pmid=27408821}}</ref><ref>{{Cite journal |last1=Fatehi |first1=Farzad |last2=Ashrafi |first2=Mahmoud Reza |last3=Babaee |first3=Marzieh |last4=Ansari |first4=Behnaz |last5=Beiraghi Toosi |first5=Mehran |last6=Boostani |first6=Reza |last7=Eshraghi |first7=Peyman |last8=Fakharian |first8=Atefeh |last9=Hadipour |first9=Zahra |last10=Haghi Ashtiani |first10=Bahram |last11=Moravej |first11=Hossein |last12=Nilipour |first12=Yalda |last13=Sarraf |first13=Payam |last14=Sayadpour Zanjani |first14=Keyhan |last15=Nafissi |first15=Shahriar |date=2021-09-21 |title=Recommendations for Infantile-Onset and Late-Onset Pompe Disease: An Iranian Consensus |journal=Frontiers in Neurology |volume=12 |pages=739931 |doi=10.3389/fneur.2021.739931 |issn=1664-2295 |pmc=8490649 |pmid=34621239 |doi-access=free }}</ref> As both hyper- and hypothyroidism disrupts muscle glycogen metabolism, it is important to keep in mind differential diagnoses and their comorbidities when trying to determine whether signs and symptoms are either [[Disease#Concepts|primary or secondary disease]].<ref>{{Cite journal |last1=Rodolico |first1=Carmelo |last2=Bonanno |first2=Carmen |last3=Pugliese |first3=Alessia |last4=Nicocia |first4=Giulia |last5=Benvenga |first5=Salvatore |last6=Toscano |first6=Antonio |date=2020-09-01 |title=Endocrine myopathies: clinical and histopathological features of the major forms |journal=Acta Myologica |volume=39 |issue=3 |pages=130–135 |doi=10.36185/2532-1900-017 |issn=1128-2460 |pmc=7711326 |pmid=33305169}}</ref><ref>{{Citation |last1=Fariduddin |first1=Maria M. |title=Hypothyroid Myopathy |date=2022-08-08 |url=https://www.ncbi.nlm.nih.gov/books/NBK519513/ |work=StatPearls [Internet] |access-date=2023-07-10 |publisher=StatPearls Publishing |language=en |pmid=30137798 |last2=Bansal |first2=Nidhi}}</ref><ref>{{Cite journal |last1=Dimitriadis |first1=G D |last2=Leighton |first2=B |last3=Parry-Billings |first3=M |last4=West |first4=D |last5=Newsholme |first5=E A |date=1989-01-15 |title=Effects of hypothyroidism on the sensitivity of glycolysis and glycogen synthesis to insulin in the soleus muscle of the rat. |journal=Biochemical Journal |volume=257 |issue=2 |pages=369–373 |doi=10.1042/bj2570369 |issn=0264-6021 |pmc=1135589 |pmid=2649073}}</ref><ref>{{Cite journal |last1=Celsing |first1=F. |last2=Blomstrand |first2=E. |last3=Melichna |first3=J. |last4=Terrados |first4=N. |last5=Clausen |first5=N. |last6=Lins |first6=P. E. |last7=Jansson |first7=E. |date=April 1986 |title=Effect of hyperthyroidism on fibre-type composition, fibre area, glycogen content and enzyme activity in human skeletal muscle |url=https://pubmed.ncbi.nlm.nih.gov/2937605/ |journal=Clinical Physiology |volume=6 |issue=2 |pages=171–181 |doi=10.1111/j.1475-097x.1986.tb00066.x |issn=0144-5979 |pmid=2937605}}</ref><ref>{{Cite journal |last=Brenta |first=Gabriela |date=2011 |title=Why Can Insulin Resistance Be a Natural Consequence of Thyroid Dysfunction? |journal=Journal of Thyroid Research |volume=2011 |pages=152850 |doi=10.4061/2011/152850 |issn=2090-8067 |pmc=3175696 |pmid=21941681 |doi-access=free }}</ref>

== Treatment ==
The muscle hypertrophy and other symptoms are reversible on treatment with [[levothyroxine]].<ref>{{Cite journal|last=Mehrotra|first=P|date=2002-03-01|title=Kocher Debre Semelaigne syndrome: regression of pesudohypertrophy of muscles on thyroxine|journal=Archives of Disease in Childhood|volume=86|issue=3|pages=224a–224|doi=10.1136/adc.86.3.224-a|pmid=11861255|pmc=1719134|issn=0003-9888}}</ref>

==References==
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{{Thyroid disease}}{{Myopathy}}

{{DEFAULTSORT:Kocher-Debre-Semelaigne Syndrome}}
[[Category:Syndromes affecting the endocrine system]]
[[Category:Syndromes affecting stature]]
[[Category:Muscular disorders]]