Hello guys, Todays presentation aims at discussing the most common syndromic causes of short stature - Turners syndrome and Downs syndrome. We have discussed the Genetics, Phenotype and co-morbidities with their individual management strategies. I hope you find it uselful too.

1. Syndromic Short
Stature
Presented by : Dr. Sonali Paradhi Mhatre

2. Basics
‘Syndrome’ refers to a group of
specific features which appear to be
unrelated, but which define a number
of disorders when they develop
together.
Dr. Sonali Paradhi Mhatre

3. Basics
• Various dysmorphic syndromes have short stature as a
component.
• In most of these disorders, the cause of short stature is
based at the cellular level.
• Growth failure may be due to either related to GH/ IGF
axis or genetic issues like SHOX insufficiency or other
unknown pathologies
Dr. Sonali Paradhi Mhatre

4. Common syndromes associated
with Short stature
Downs
syndrome
Turners
Syndrome
Noonans
Syndrome
Silver Russel
Syndrome
Prader willi
syndrome
Williams
syndrome
Aarskog
Scott
syndrome
Kabuki
syndrome
Smith-Lemli-
Opitz
syndrome
Rubinstein
Taybi
syndrome
Bloom
syndrome
Seckel
syndrome
Costello
syndrome
Cardio-facio-
cutaneous
syndrome
Brachmann-
de Lange
syndrome
Şıklar Z, Berberoğlu M. Syndromic disorders with short stature. Journal of clinical research in pediatric
endocrinology. 2014 Mar;6(1):1.

5. Common syndromes associated
with Short stature
Downs
syndrome
Turners
Syndrome
Noonans
Syndrome
Silver Russel
Syndrome
Prader willi
syndrome
Williams
syndrome
Aarskog
Scott
syndrome
Kabuki
syndrome
Smith-Lemli-
Opitz
syndrome
Rubinstein
Taybi
syndrome
Bloom
syndrome
Seckel
syndrome
Costello
syndrome
Cardio-facio-
cutaneous
syndrome
Brachmann-
de Lange
syndrome
Şıklar Z, Berberoğlu M. Syndromic disorders with short stature. Journal of clinical research in pediatric
endocrinology. 2014 Mar;6(1):1.

6. Turners
Syndrome

7. Turner syndrome
 One of the most frequent chromosome aberrations in
females.
 Incidence: 50 per 100000 girls.
 Named after Henry H. Turner (Okhlahama) in 1938 who
described syndrome.
 Original description focussed on Infantilism, cubitus
valgus and congenital webbing of neck.
Later, additional characteristics and abnormalities
were described.
 Most gestations affected by X chromosome monosomy (45,X) do not
survive to birth

8. Turner syndrome - GENETICS
 The genetic background for Turners syndrome is highly
variable, but includes anamolies of Sex chromosome.
 Types of chromosomal anomalies:-
1. 45,X (monosomy X)(~45%)
2. 45,X/46,XX or 45,X/47,XXX
Presence and degree of mosaicism may differ among different
tissues.
3. Structurally abnormal X chromosome
2 copies of the long arm of the X chromosome connected head-to-
head / Ring chromosome X (rX) / Xp or Xq deletion / Deletion of a
portion of the short arm of the X chromosome

9. Turner syndrome - GENETICS
Monosomy Mosaicism

10. C
L
I
N
I
C
A
L
F
E
A
T
U
R
E
S
Gravholt CH. Epidemiological, endocrine and metabolic features in Turner syndrome. European journal of endocrinology. 2004 Dec 1;151(6):657-88.

11. Turner syndrome :
Clinical Presentation

12. Turner syndrome :
Clinical Presentation

13. Turner syndrome – Short stature
 Short stature is almost always present in turners syndrome.
 Evidence suggests that the estimated adult height is
approximately 20cm shorter than controls of same ethnicity.
 Reasons:-
1. Growth is mildly retarded already in utero.
2. Subnormal growth in early childhood.
3. Normal pubertal growth spurt is virtually absent.
 Causes implicated :-
1. Haploinsufficiency of SHOX gene.
2. Reduced GH/ IGF activity (Esp Pubertal GH secretion and IGF1
rise is absent)
3. Skeletal maturation by gonadal estrogens deficient.

14. Turner syndrome – Short stature
Management
 It is recommended that all girls with short stature and/or growth
delay for which no medical reason can be found to have a
Karyotype performed in order to investigate the possibility of
the presence of TS.
 The growth impairment in the majority of TS individuals
therefore, is not due to GH deficiency although a small minority
of TS girls may manifest classic GH deficiency (abnormal GH
concentrations after pharmacologic provocation) in addition to
their abnormal karyotype.
 Psychological studies of children with TS report that their short
stature is most often associated with social competence.

15. Turner syndrome – Short stature
Management
 Factors that seem to be most predictive of taller adult
stature in TS individuals are related to the following:
(1) Taller mean parental height
(2) Taller height at initiation of therapy,
(3) The response to hGH during the first year of therapy,
(4) Mean dose of hGH/week,
(5) Taller height at the start of puberty
(6) Age at the start of puberty

16. Turner syndrome – Short stature
Management
1.Recombinant human GH (hGH) therapy is now routinely used
to treat the growth impediment in girls with TS.
2.Which hGH dose to use is still an issue of debate but
recombinant hGH therapy is usually started at the recommended
dose of 0.375 mg/kg/week divided into daily injections which is the
dose approved by the US Food and Drug Administration.
3.Most studies have shown that the final height of girls with TS
seems to be maximized when estrogen therapy is combined with
hGH. The optimal age of the initiation of estrogen therapy is at a
normal pubertal age around 12 years of age.
4.Therapy using oxandrolone at a usual dose of 0.05 mg/kg/day is
used mostly in TS patients with extreme short stature who start
hGH therapy after 9 years of age.

17. Turner syndrome –
Cardiac morbidities
 Most of the increased morbidity and mortality in Turner
syndrome is attributable to different heart conditions.
 Malformations generally involve only the vessels of the left side
of the heart with characteristic pattern.
 Most common finding : Bicuspid aortic valve.

18. Turner syndrome –
Cardiac morbidities

19. Turner syndrome –
Cardiac morbidities
 Most of the increased morbidity and mortality in Turner
syndrome is attributable to different heart conditions.
 Malformations generally involve only the vessels of the left side
of the heart with characteristic pattern.
 Most common finding : Bicuspid aortic valve.
 The other cardiac problems include:
1. Structural – Coarctation of Aorta, Aortic dilatation, dissection,
aberrant Right subclavian artery, etc.

20. Turner syndrome –
Cardiac morbidities

21. Turner syndrome –
Cardiac morbidities
 Most of the increased morbidity and mortality in Turner
syndrome is attributable to different heart conditions.
 Malformations generally involve only the vessels of the left side
of the heart with characteristic pattern.
 Most common finding : Bicuspid aortic valve.
 The other cardiac problems include:
1. Structural – Coarctation of Aorta, Aortic dilatation, dissection,
aberrant Right subclavian artery, etc.
2. Hypertension (30% are mild HTN / 50% abnormal diurnal
variations in BP).
3. ?? Rising incidence of IHD (as per recent studies).

22. Turner syndrome – Cardiac morbidities
Gravholt CH. Epidemiological, endocrine and metabolic features in Turner syndrome. European journal of endocrinology. 2004 Dec 1;151(6):657-88.

23. Turner syndrome – Sexual Maturity &
Fertility
 Carr et al. (1960)n had proved that the germ cell count in
fetusses with TS was normal till 18 wks gestation.
 This was followed by an ‘Accelerated degeneration’ of germ
cells – Resultant ‘STREAK GONADS’ & infertility.
 Gonadal insufficiency forum to be associated with high levels of
FSH & LH in early childhood and puberty.
 Pubertal gonadotrophin pulse periodicity of FSH and LH was
absent.
 Approx 20-30% TS females may show some signs of puberty
spontaneously.

24. Turner syndrome – Sexual Maturity &
Fertility
 Treatment includes:-
1. Endocrine therapy for pubertal induction in conjunction with the
patient’s peers (to psychosocial health).
2. Initial low dose Estrogen (as monotherapy) --- f/b Gestagen
addition when breakthrough bleeding occurs.
o Estrogen therapy to be coordinated with the use of GH.
o Only regimens with continuous estrogen exposure to be used,
since TS women become absolute estrogen depleted if ‘pill free
week’s regimen is used.
3. In studies: Early Estradiol substitution to rescue oocytes from
apoptosis / Germ cell cryopreservation

25. Turner syndrome – Skeletal
Features
 Turner syndrome is a syndrome of disproportionate
anthropometry and body composition.
 Growth retardation is via longitudinal axis and horizontal
measurements are comparable to control females.
 Ht / sitting wt/arm span  reduced
 HC / biacromial and biiliac diameter  comparable to peers
 BMI / waist:hip ratio / fat mass  increased.
 Osteoporosis

26. Turner syndrome – Skeletal
Features
Gravholt CH. Epidemiological, endocrine and metabolic features in Turner syndrome. European journal of endocrinology.
2004 Dec 1;151(6):657-88.

27. Turner syndrome – Skeletal
Features
 Turner syndrome is a syndrome of disproportionate
anthropometry and body composition.
 Growth retardation is via longitudinal axis and horizontal
measurements are comparable to control females.
 Ht / sitting wt/arm span  reduced
 HC / biacromial and biiliac diameter  comparable to peers
 BMI / waist:hip ratio / fat mass  increased.
 Osteoporosis
 Cervical vertebral hypoplasia, Scoliosis(10%)
 Short 4th Metacarpal bones
 Cubitus valgus / Genu Valgus
 Madelung deformity

28. Turner syndrome – Skeletal
Features

29. Turner syndrome –
Endocrinological Problems
 Impaired glucose tolerance & diminished insulin sensitivity,
Prediabetic state.
 Thyroid Dysfunction – Hypothyroidism / Thyroid antibody
formation  reqire treatment.
 Adrenal function is normal. Adrenarche found to be earlier in
TS.
 Androgen insufficiency - treated with Oxandrolone.

30. Turner syndrome –
Miscellaneous
 Elevated hepatic enzymes.
Cirrhosis frequent in women with TS.
 Recurrent Middle ear infections
Sensorineural hearing loss.
 Poor thriving during the first postnatal year
 Average to low-average full-scale intelligence quotient
 Uneven cognitive profile with verbal skills tending to be
significantly higher than nonverbal skills is often considered
to be the hallmark of cognitive ability in TS.

31. Turner syndrome –
Miscellaneous
 Deficits on visual-spatial tasks
(Right-left disorientation and difficulty with design copying)
 Problems with Executive skills
(Impaired attention and concentration, problem-solving ability,
organization, working memory, behavioral control and use of
goal-directed strategies, as well as increased impulsivity and
slower processing speed.
 Increased risk for Attention Deficit Hyperactivity Disorder
 Adolescent girls with TS are at greater risk for having problems
related to lower social activity, poor social coping skills and
increased immaturity, hyperactivity and impulsivity compared to
their peers.

32. Downs
Syndrome

33. Downs Syndrome
 Down syndrome (DS) is the most
common chromosome abnormality
among liveborn infants.
 DS is characterized by a variety of
dysmorphic features, congenital
malformations, and other health
problems and medical conditions.
 Characteristic dysmorphic features
predominantly affect head, neck
and extremities.
 Associated with short stature,
Intellectual disability, behavioural
and psychiatric disorders, cardiac
disorders, vision & hearing
problems, etc.

34. Downs Syndrome - Genetics
1. Trisomy 21 (95 %)
Instead of the normal number of 46 chromosomes in each cell,
the individual with Down syndrome has 47 chromosomes.
2. Translocation (3 - 4 %)
Extra 21 chromosome is attached or translocated on to
another chromosome, usually on chromosome 14, 21 or 22.
3. Mosaicism (1 %)
Some cells have 47 chromosomes and others have 46
chromosomes.
4. Nondisjunction

35. Downs Syndrome - Genetics
Trisomy 21

36. Downs Syndrome - Genetics
Non-Dysjunction Mosaicism
Translocation

37. Advanced maternal age – Risk of Downs
Maternal Age Risk
15 – 29 yrs 1 : 1500
30 – 34 yrs 1 : 800
35 – 39 yrs 1 : 270
40 – 45 yrs 1 : 100
45 and above 1 : 50

38. Downs Syndrome:
Antenatal Diagnosis

39. U
L
T
R
A
S
O
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N
D
Downs Syndrome:
Antenatal Diagnosis

40. Downs Syndrome:
Antenatal Diagnosis
Raniga S, Desai PD, Parikh H. Ultrasonographic soft markers of aneuploidy in second trimester: are we lost?. Medscape General Medicine. 2006;8(1):9.

41. Downs Syndrome:
Halls criteria
Criteria useful for diagnosis of Downs syndrome in
neonates:
1. Poor Moro reflex (85%)
2. Hypotonia (80%)
3. Flat facial profile (90%)
4. Upward-slanting palpebral fissures (80%)
5. Morphologically simple, small round ears (60%)
6. Redundant loose neck skin (80%)
7. Single palmar crease (45%)
8. Hyperextensible large joints (80%)
9. Pelvis radiograph morphologically abnormal (70%)
10.Hypoplasia of fifth finger middle phalanx (60%)
Hindley D, Medakkar S. Diagnosis of Down’s syndrome in neonates. Archives of Disease in Childhood-Fetal and Neonatal Edition. 2002 Nov 1;87(3):F220-1.
v

42. Downs Syndrome:
Dermatoglyphics
Rajangam S, Janakiram S, Thomas IM. Dermatoglyphics in Down's syndrome. Journal of the Indian Medical Association. 1995 Jan;93(1):10-3.

43. Downs Syndrome

44. Downs Syndrome

45. Downs Syndrome
Clinical
Pictures

46. Intellectual
disability
&
Neurobehaviou
ral issues
Dental problems
Dysmorphic
features
Growth
retardation
&
Short
stature
Hearing loss
Heart
Disease
Endocrine
Disorders
Hematolo-
-gical
disorders
Gastrointestinal
abnormalitiesEye Problems
Urogenital
disorders
C
O
M
O
R
B
I
D
I
T
I
E
S

47. Downs Syndrome:
Intellectual disability & Neurocognitive
disabilities
 Cognitive impairment seen in all individuals with DS. Most with mild to
moderate IQ (50 to 75 range)
 Developmental impairment apparent in the first year of life with delayed
milestones.
 IQ declines through first 10 years of life, reaching plateau in adolescence
and adulthood.
 Adults with DS develop neuropathological and functional changes, typical
of Alzheimer's – noted by 4th - 5th decade of life.
 Disruptive behavioral disorders like ADHD, Conduct disorders or
aggressive behaviors common.
 Autism is a common co-morbidity of Downs syndrome.

48. Downs Syndrome:
Growth retardation & Short
stature
 Birth weight, length & Head circumference are less in DS.
 Growth rate is reduced in DS compared to peers, especially in
infancy and adolescence.
 Growth is most reduced in children with heart diseases.
 Cause of DS associated growth retardation – Unknown
 Few case reports of low IGF1 and diminished spontaneous GH
secretions reported. But no GH deficiency proven.
 Obesity - Weight is less than expected for length in DS infants,
and then increases disproportionately. So, majority of children
are obese by age 3-4 yrs.

49. Downs Syndrome:
Heart Disease
 Approx 50% DS children have Congenital heart disease.
 In adulthood, valve abnormalities are reported (Commonest mitral valve
regurgitation).
Heart Disease Prevalence
Atrioventricular septal defects /
Endocardial cushion defects
45%
VSD 35%
Isolated ASD (secundum) 8%
Isolated PDA 7%
Isolated Tetralogy of Fallots 4%
Other (eg vascular rings) 1%
Allen EG, Freeman SB, Druschel C, Hobbs CA, O’Leary LA, Romitti PA, Royle MH, Torfs CP, Sherman SL. Maternal age and risk for trisomy 21 assessed by the origin of chromosome nondisjunction: a report from the Atlanta and
National Down Syndrome Projects. Human genetics. 2009 Feb 1;125(1):41-52.

50. Downs Syndrome:
Gastrointestinal Problems
Duodenal atresia or
stenosis
± Annular pancreas
(20-28%)
Imperforate anus
(2-3%)
Celiac disease
(5-16%)
Hirschsprungs
disease
(2%)
Esophageal atresia +
Tracheoesophageal
fistula
(5-10%)
Ostermaier KK. Down syndrome: Clinical features and diagnosis. UpToDate: UpToDate, Post TW (Ed), UpToDate. Waltham. Accessed Feb. 2019;4:2018.

51. Downs Syndrome:
Eye features
 Up-slanting(mongoloid
slant)
 Myopia, hypermetropia
 Strabismus
 Brushfield spots
 Cataracts
 Glaucoma
 Keratoconus, blepharitis
 Hypertelorism
 Medial epicanthal folds
 Nystagmus
https://www.ndss.org/resources/vision-down-syndrome

52. Downs Syndrome:
Hearing loss
 Hearing impairment affects 38 – 78 %
individuals with Downs syndrome.
 Common issues:
1. Sensorineural hearing loss
2. Conductive hearing loss
3. Mixed haring loss
4. Otitis media (50-70%)

53. HYPOTHYROIDISM
(3 - 54%)
Includes primary
congenital
hypothyroidism,
acquired
hypothyroidism,
transient
thyrotropeinemia
Hyperthyroidism
(2%)
Thyroid
disease
Risk of Type 1 DM
increased
Evidence suggests
risk in DS children
can be 3 times
higher.
Diabetes
Downs Syndrome:
Endocrinological abnormalities

54. Downs Syndrome:
Hematological disorders
 Polycythemia (approx. 65 % downs neonates)
 Macrocytosis, Higher hematocrits.
 Leukopenia and thrombocytosis have been reported in isolated
studies.
 Risk of leukemia is 1 – 1.5% in DS.
Transient
Myeloproliferative
disease
Acute
Megakaryoblastic
Leukemia
Acute
Lymphoblastic
leukemia
Types Of Leukemia in Downs syndrome

55. Downs Syndrome:
Hematological disorders
 Transient leukemia (Transient myeloproliferative
disease):
o Almost exclusively affects DS babies(20%).
o Majority are asymptomatic and spontaneously resolve by 2-3
months of age, although some may develop serious disease.
o Has presence of ‘blast’ in peripheral blood. Hb and TLC is
normal.
o Platelet counts vary
o % of blast is lower in marrow than peripheral blood and BM
cytogenetics reveal no clonal abnormality, except trisomy 21.

56. Downs Syndrome:
Hematological disorders
 Acute Megakaryoblastic Leukemia:
o Approx 26% transient leukemics form Acute megakaryoblastic
leukemia (FAB M7 subtype of AML or AML-M7)
o Incodence - Approx 1 per 50-200 DS children
o Develops in first 4 yrs of life.
o Associated with mutations in GATA1 (Mutations absent in >4yr
patients)
o Majority present with Myelodysplastic syndrome
(thrombocytopenia f/b anemia)
o High initial treatment related mortality.

57. Downs Syndrome:
Hematological disorders
 Acute Lymphoblastic Leukemia:
o Risk of developing ALL is 10 – 20 times higher in DS children.
o 1-3 % of ALL are seen in DS children.
o Leukocyte counts, leukemic mass, Age distribution and
immunophenotype were similar in DS and Non- DS ALL.
o Mediastinal mass, CNS leukemia and unfavourable prognostic
signs like (9;22) ot t(4;11) translocations less in DS –
suggesting favourable outcomes.
o Good response to chemotherapy

58. Downs Syndrome:
Other system involvement
PULMONARY
Obstructive Sleep Apnea (30-75%)
Asthma
Pulmonary vasculature disorders,
Parenchymal lung disease
Chronic aspirations
Recurrent respiratory tract infections
DERMATOLOGY
Palmoplantar hyperkeratosis (41%)
Seborrhagic dermatitis (31%)
Fissured tongue (20%)
Cutis marmorata (13%)
Geographic tongue (11%)
Alopecia areata (8%)
REPRODUCTION
Women with DS are fertile.
Nearly all males with DS are infertile
spermatogenesis impairment)

59. Downs Syndrome:
Other system involvement
Urologic Abnormalities
Hypospadias (1 in 250)
Cryptorchidism (14 -27%)
Testicular cancer
Renal malformations (3.5%)
ATLANTOAXIAL INSTABILITY (13%) may lead to subluxation of cervical
spine and cord compression (2%)
DS Arthropathy (8-10 /1000) Oligo/poyarticular
Immune Deficiency
Chemotactic defects
Decreased IgG4 levels
Quantitative and qualitative
abnormalities of T & B cells in the
first years of life.

60. Downs Syndrome: Screening Schedule

61. Common syndromes associated
with Short stature
Downs
syndrome
Turners
Syndrome
Noonans
Syndrome
Silver Russel
Syndrome
Prader willi
syndrome
Williams
syndrome
Aarskog
Scott
syndrome
Kabuki
syndrome
Smith-Lemli-
Opitz
syndrome
Rubinstein
Taybi
syndrome
Bloom
syndrome
Seckel
syndrome
Costello
syndrome
Cardio-facio-
cutaneous
syndrome
Brachmann-
de Lange
syndrome
Şıklar Z, Berberoğlu M. Syndromic disorders with short stature. Journal of clinical research in pediatric
endocrinology. 2014 Mar;6(1):1.

62. To be
continued in
the next
session……

63. Thank
You