GROWTH HORMONE

The majority of children with Kabuki will fall in the lower percentile for growth. Postnatal growth retardation means the children are usually born with normal body lengths but their growth following birth is at a slower rate than the norm. The causative factors for growth retardation in Kabuki syndrome have not yet been clarified. Some children, when tested, have shown partial growth hormone level deficiencies and have been given growth hormone injections for varying lengths of time. It appears that for some of these children with proven growth hormone deficiencies, the therapy has helped them attain increased linear growth.

Growth is infuluenced by the endocrine system.

There are a percentage of children with Kabuki who have endocrinological abnormalities.

What exactly is the endocrine system?

The endocrine system consists of various glands which produce hormones which are delivered directly into the blood. Each of the glands of the endocrine system has one or more specific functions, but they are all dependent upon one another to maintain a normal hormonal balance in the body.

The pituitary gland (also called the hypophysis in the articles), which is about the size of a pea, lies at the base of the brain and is called the master gland because it regulates the functions of other endocrine glands. It also has some functions of its own such as controlling the body's growth through the growth hormone.

Some pituitary hormones that directly affect other glands are:

1)thyroid-stimulating hormone (TSH), which stimulates the thyroid gland

2)adrenocorticotropic hormone (ACTH), which affects the adrenal gland

3)the gonadotropic hormones (FSH, LH, and LTH), which have a role in the development and proper functioning of the gonads (ovary and testes)

Number 1, the thyroid gland, is situated in the neck and produces hormones that are vital in maintaining normal growth and metabolism. It also stores iodine.

Number 2, the adrenal glands, are situated above the kidneys and secrete at least 26 hormones, including epinephrine, corticosterone, and aldosterone. They are vital to the protection of the body during stress and danger, and to the adaptation of the body to changes in its environment.

Number 3, the gonads (or sex glands), consist of the testes in the male and the ovaries in the female. Besides producing sperm and ova, they manufacture the androgens and estrogens, hormones responsible for the special characteristics of the male and female.

Another group of cells belonging to the endocrine system are the specialized cells scattered throughout the pancreas, called the 'islands of Langerhans'. These cells secrete the hormone insulin, which is necessary for proper utilization of carbohydrates - therefore decreasing blood sugar. The cells also secrete glucagon, a hormone that has the opposite effect of insulin in that it stimulates glycogenolysis in the liver (changing carbohydrates into glucose) - therefore increasing blood sugar.

So now that we understand a little what the endocrine system consists of, what does this mean in reference to Kabuki?

Well, it doesn't seem unlikely that since endocrinological abnormalities have been associated with Kabuki that we should see a whole range of hormonal-dependent abnormalities, including precocious puberty, growth retardation, diabetes, etc. But I don't think the professionals know yet what triggers the endocrine anomalies.

Because the glands of the endocrine system are so dependent upon one another, where do the problems lie? What mechanisms are causing the anomalies? Hopefully, by testing, by documenting, and by publishing the results, we will eventually find some answers.

 

Genetic Articles on Growth Hormone:

Long-term hormone replacement therapy in two patients with Kabuki syndrome and growth hormone deficiency - Minerva Pediatr Jan-Feb;52(1-2) pp. 47-53 2000 Author: : Gabrielli O, Carloni L, Coppa GV, Bedeschi MF, Petroncini MM, Selicorni A

Growth Hormone Deficiency and Premature Thelarche in a Female Infant with Kabuki Makeup Syndrome - Hormone Research 43 pp.303-306 1995 Author: Devriendt K, et al

A case of Kabuki make-up syndrome with central diabetes insipidus and growth hormone neurosecretory dysfunction - Acta Paediatrica Japonica 36 pp.412-415 1994 Author: Tawa R, et al.

A Case of Kabuki Make-Up Syndrome Associated with Growth Hormone Deficiency - Clinical Pediatric Endocrinology 2 pp. 13-16 1993 Author: Satoh M, et al

Growth Hormone Insufficiency in Kabuki Make-up Syndrome - Acta Paediatrica Scand (Suppl) 370 pp.196 1990 Author: Kawada Y, et al.

Following is a quote from the article, Growth Hormone Deficiency and Premature Thelarche.....

Quote:

At birth this girl was of normal size, but a marked growth failure was observed during infancy. Repeated GH (growth hormone) stimulation test consistently showed a lowered GH response (below 10 ng/ml), suggestive of partial GH deficiency. The neonatal hypoglycemia, truncal obesity, depressed serum T3 concentrations, undetectable IGF-I levels and the remarkable growth response to rhGH therapy corroborate the diagnosis of GH deficiency. The impressive response to exogenous GRF (growth hormone-releasing factor) indicates that the GH deficiency is of hypothalamic origin, possibly due to GRF deficiency. In this regard, it is of particular interest that the pituitary stalk appeared to be intact on magnetic resonance imaging (MRI),and that no major malformations of this region could be demonstrated.

Postnatal growth deficiency is a major criterion of the KMS as the reported incidence is 80%. In this girl with the KMS the postnatal growth retardation was documented to be caused, at least in part, by GH deficiency. Two other patients with KMS and partial GH deficiency have been reported, one of whom was treated with GH apparently without significant effect.

This girl presented premature breast development without other signs of systemic estrogen effect, i.e. no macroscopic vulvar estrogenization, no growth acceleration or advanced bone age. Neither was there axillary or pubic hair development. In addition, breast size did not augment over a period of 2.5 years. The basal serum FSH level was elevated with a normal basal LH level and predominant FSH response to LH-RH administration was present. These clinical and biochemical findings are consistent with the diagnosis of premature thelarche. Premature thelarche is a variant of precocious sexual maturation, and can be caused by an activation of the hypothalamopituitary axis, resulting in a predominant FSH secretion, as in this patient. It has been suggested that true central precocious puberty and premature thelarche represent the extreme variants within the spectrum of precocious hypothalamopituitary activation. in the review study of Niikawa et al., premature thelarche was present in 23% of the girls with KMS. Endocrinological studies have been reported in three patients; two of them appear to present isolated premature thelarche, whereas the third was documented to have true central precocious puberty. The precise etiology of the precocious sexual maturation in KMS girls is currently unknown.

In this girl, no deficiencies of other pituitary hormones were identified. interestingly, a boy with the KMS and both central diabetes insipidus and GH neurosecretory dysfunction has recently been reported. The coincidence of premature thelarche and growth hormone deficiency in this girl and the occurrence of hypothalamopituitary dysfunction in other children with the KMS warrant further neuroendocrine studies in children with the KMS.

Unquote

So it seems they're saying that this particular girl had early breast development (thelarche), but no other signs of early puberty (precocious puberty). And that in other studies done previously by Niikawa, 23% of the girls had premature thelarche. Of those girls, 3 had endocrinlogical studies done (blood drawn to detect various hormonal levels) which showed 2 had only early breast development and 1 had 'true central precocious puberty'. I'm not sure what's meant by 'true', but I'm assuming it means the girl had not only early breast development, but also all other signs of puberty (increased growth, widening of hips, appearance of axillary and pubic hair, and the onset of menstruation).

They conclude that the precise cause of the premature sexual maturation is not currently known, but that the fact that so many children are showing endocrine-based anomalies warrants further studies.

 

Family Contacts for Information on Growth Hormone Injections:

Carr, Scott & Theresa

9219 Old State Rd.

Evansville, Indiana 47711

USA

Email: skitch@evansville.net

Sibert, Marty & Sarah

872 Ravine Terrace Dr.

Rochester Hills, Michigan 48307

USA

Ph #248-651-7205

Email: ses032655@aol.com

Family's Past Discussions (Via KSN's Email Mailing List) On Growth:

Date: Tue, 21 Sep 1999 22:24:08 EDT

[...] Also, we talked to Dr. Wilson who diagnosed Klaudia

about her growth rate drop; he said not to worry unless she has another big

drop and then we might consider growth hormones.

So can someone tell me what the growth rate is like for children with Kabuki.

What should I consider "normal." Has anyone experienced this type of

drastic drop?

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Date: Thu, 30 Sep 1999 19:08:49 -0500

I am new to the KSN network. I have a daughter Zoe, 6 years old with Kabuki.

I recently read from Dr. Biavati that these children usually have weaker

immune systems. Our daughter has no fluid in her pituitary cavity which

makes her growth hormone defficient. I am amazed at the what other benefits

there seem to be with Growth Hormone injections, and if any other parents

have experienced the same. When Zoe has a cut or scrap she seems to heal

overnight and the wound is completely gone in a day or two. Also she rarely

gets sick, There might be 3 or 4 of us in the house with the flu and she

will never get it. She has had ear infections but rarely any other sickness.

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Date: Thu Apr 27, 2000 5:49pm

>>"Is there really an incidence of obesity following this

period of low weight?"

I doubt very much that children who have been very tiny and 'underweight'

will become obese in teenagehood. Whenever a new syndrome is described -

every characteristic is recorded. This is to see if there is a pattern -

do many of the children have the same? Sometimes characteristics may be

noted that are really not a part of the syndrome, but may be a part of the

familial genetics. But often this will not become known until a great deal

of documenting and time has passed by. So it's still not really known

whether the weight gains of the few teenagers was because of the syndrome

or because of some other reason.

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Date: Sun Jun 11, 2000 8:47am

Children are constantly doubting that she is 9 years old, because of her size and her slow running. She is very frustrated with these continual inquiries and observations from the other children.

I have thought of "ISN'T IT GREAT THAT WE ALL ARE DIFFERENT? " or

"GOOD THINGS COME IN SMALL PACKAGES" ......

......but could use some suggestions before I talk to her about it.

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Date: Mon Jun 12, 2000 10:35am

I think it is a little easier having a girl who is smaller. People

constantly ask me how old Shannon is and when I answer 6 they always look surprised and

would usually say something like "she only looks 4", or "she's so

tiny". This is hard for her to hear because she wants to be such a big

girl. So now I answer right away with " She's 6, my petite girl with a

big heart". Most people get the idea right away not to say anything

else about her size.

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Date: Mon Jun 12, 2000 8:01am

Jonathans reply is I'm 10 and still growing!

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Date: Mon Jun 12, 2000 6:40pm

Ian says I'm growing everyday!

Ian is going to be 8 on the 23rd of this month.

When people comment I just smile and say, yes he is!

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Date: Tue Jun 13, 2000 5:17pm

My late daughter, who had Down syndrome, was also destined to be tiny

because of the syndrome. She had the teeniest feet at age 6 (still wore

toddler size). I said the same thing, proudly: "She is my petite little

girl." Is there some shame nowadays in being small?? She was born at only

5 lbs., 17 inches. At least my sister (whose oldest son was a 10-pounder)

would tell me I was lucky because I had a baby; while she had a COW! Now,

Derek (so far) isn't all that small for a K.K. At age 8, he is about 4 feet

or so tall and 72 pounds (we're gonna have to watch his weight, I think).

Besides, I don't care, 'cause my own dad was only 5' 4" and weighed about

140 soaking wet. My sister & I were taller. It really gets funny when kids

are in middle school & growing at vastly different rates! Have you ever

looked at the size differences then? What a riot! [...]

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Date: Mon Aug 14, 2000 6:17pm

For those of you with little ones with smaller stature, was that

something that was apparent even early on in measurement's taken at doctor's

appointments? Like length, etc.? [...]

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Date: Mon Aug 14, 2000 1:11pm

[...] Going on the assumption that he has K.S. , he has always been small. Not

incredibly so, but being a month early he has nevr quite gotten to be the

size of a "normal" kid his age. Having a really hard time putting and

keeping weight on him also. Sorry couldn't be more help; Still kinda new at

all this.

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Date: Tue Aug 15, 2000 00:21am

As mother to Hannah who is now 5 I will reply. Hannah is short for her size but has been fed via a gastrostomy since 7 weeks of age therefore is only just under her "normal" size. [...]

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Date: Tue Aug 15, 2000 8:08am

Our daughter, Kimberly, turned 9 years old last month. Physically she is the size of a 5-6 year old. She was small at birth (full term) and gained weight slowly from the very beginning. She never had a feeding tube.

When the doctor and nurses charted her height, weight and head size on the growth charts, Kimberly was always below or on the bottom line. [...]

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Date: Tue Aug 15, 2000 5:30am

I asked a GP about growth hormone. Even tho Steve is very short for 10, the

doc thought the hormone was not necessary. I suppose it has to be injected,

which is not a pleasure for Steve. Has anyone had that experience?

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Date: Tue Aug 15, 2000 4:38pm

Angie (5 yrs.) had a physical today and her G.P said that even though she is very small -under 5th percentile for height and weight- she is following the curve and we needn't worry. She said that if there was a growth hormone problem the line would flatten out.

Most of what I've read says the growth delay starts after the first year but Angie was only 2 1/2 lbs at birth(full term). She had feeding difficulties but no G tube. Today she was 35 1/2 inches tall and 30 3/4lbs. Her growth is very slow but steady.

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Date: Sun Aug 27, 2000 10:17pm

There have been several items in the KSN e-mail lately that are similar

to our experiences with our son, Alan, now 12.

Alan was small at birth (5lbs 13oz), and stayed below the 5th percentile

in height and weight for years. A few years back he gained weight, and

is now rather stocky. His weight seems to have stabilized, and he is

still getting taller, slowly. He is about 4 feet three inches tall now.

We discussed growth hormone with his doctor several years ago. I think

we were told that it is very expensive (about $10,000 per year), and

requires a daily injection in each leg. Long term effects arenít known,

and growth hormone produces a strange elongated growth in kids who are

short for some reason other than lack of growth hormone. So we decided

to leave well enough alone. [...]

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Date: Wed Sep 13, 2000 3:30am

Hi everyone! You gotta remember, too, that KK's who have a heart defect,

either repaired or unrepaired, may always be skinny and/or small. Also,

KK's seem to have more digestive problems or hypersensitivities to food

textures, etc., hence the necessity of feeding tubes in early life. My past

experience with KK's has been that almost all have the tube removed at some

point and go on to eat normally. But due to heart defects, as stated above,

they remain small and/or skinny.

My son has a (relatively) minor heart defect that may or may never need

repair when he is an adult; what we've found with him is, he is slightly

overweight right now. He gets lots of exercise, too, he's very active. But

he's a little on the short side. It's not enough to worry about at this

point.

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Date: Thu Nov 16, 2000 4:46pm

I'm trying to get a grip on postnatal growth deficiency. Can you please let

me know how tall and how much your kids weigh at 1, 2, etc., so I can

compare.

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Date: Fri Nov 17, 2000 00:15am

Here are Jakes stats

Birth: weight 4140gms length 54cm Head circ 34.3cm

6months: weight 8650gms length 69.5cm Head circ 43cm

12months weight 11kg length 78cm Head circ 45.8cm

18months weight 11.22kg length 87.4cm Head circ 47.9cm

2.5years weight 15.1kg length 100.1cm

4.5years weight 18kg length 108cm

Doctors say Jakes growth rate seems to be excellerating slightly, where as

for a long time he was in the average range.

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Date: Fri Nov 17, 2000 8:11am

My son, Mitchell, has always been in the 5th percentile for height and

weight for his age group. He is now 8 1/2 years old and still only weighs

42 lbs. My other son, who just turned 5 years old, weighs about the same

and is only 1 to 2 inches shorter and is catching up fast.

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Date: Fri Nov 17, 2000 12:51pm

After Nathan's coarc repair he finally got near the bottom of the growth

charts, instead of being off the bottom of the paper. By 3 he had gotten up

to 36 pounds. He stayed 36-38 pounds until he was 7 and a new medication

(risperdal) put 15 pounds on him in a little over a month. Now he has been

stable at 52-54 pounds for almost 3 years. He is a little lighter and

shorter than his brother who is 2 years younger than him.

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Date: Fri Nov 17, 2000 12:56pm

My son which is now seven 1/2 has always been in the 50th percentile, which means a growth that can be compared to the average of all the children but two yars ago he "stopped" for a certain period.That time then went over. One of the features of KS is the growth deficiency, so you are doing it right to follow this matter. Don't worry too much if the growth sometimes seem to slow down, things may change.

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Date: Fri Nov 17, 2000 6:47pm

My son Loren whose almost 6 has been in the 5th

percentile for weigt since he was 2 1/2, 10th percent

for height. He weights 33 lbs.

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Date: Mon Nov 20, 2000 1:13am

My son Ian has grown over 12 inches since we started growth hormone.

I would add that Ian was flat lining...there was no curve!

After 2 1/2yrs. he is now in the 5th % on the charts. [...]

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Date: Mon Nov 20, 2000 2:29pm

[...] Our Murrandah is 2 and 3mths old he now weighs 9kg.......His weight gain is very slow indeed . He was examined in July by a professor in Salt Lake City for the other syndrome he has Opitz C and at that time his length was 77cm which gives him a height of a 13mth old,Weight was 8.7 which is 8 mth old & his head circumference was 46.2 which is of a 10 mth old baby. [...]

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Date: Mon Nov 20, 2000 11:09pm

[...] As for size, since the g-tube was put in last January, Caleb has gone from being way below the charts to the 25th percent for height and the 15th percent (and climbing) for weight. His head circumference is still just below the 5th. He is about 25 lbs right now and 33.5 inches long and let me tell you, my back and arms are screaming for Caleb to start walking!! [...]

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Date: Tue Nov 21, 2000 8:30am

At 5 years our little Angie is usually taken for a two year old. She has grown about 4 inches in the past 3 years and is 36 inches tall.She weighs 30 pounds so she is below the 5th %. [...]

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Date: Tue Nov 21, 2000 6:32pm

Kristi-Leigh sounds like Angie, she is 6 and is taken for 2 1/2 yr old. Kristi-Leigh weighs 30 pounds and has been that since last december and is 38 inches tall. [...]

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Date: Fri Nov 24, 2000 6:57am

This is Angela (mother to Mila to be 2 tomorrow). Mila

sounds so much like the other children described in this series of

notes on weight gain. Mila was almost 17.5 pounds and recently lost

.5 pound due to a cold. She is about 31 inches tall and she always

gets mistaken for a one year old. [...]

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Date: Fri Dec 1, 2000 1:08pm

Regarding my sons Growth Hormone:

My son Ian receives his injection at night when he is asleep.

It wasn't worth the fight.

But we only tried it because he wasn't growing at all!!!!!!!!!

Today he is in the 5th%

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